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Tamara Vyshkina1 and Bernadette Kalman1,2Received 12 March 2008; Revised 21 April 2008; Accepted 25 April 2008; Published online 2 June 2008.Top of pageAbstractNeurodegeneration develops in association with inflammation and demyelination in multiple sclerosis. Available data suggest that the progressive neuroaxonal loss begins in the earliest stages of the disease and underlies the accumulation of clinical disability. The loss of neurons and their processes is driven by a complex molecular mechanism involving cellular and humoral immune histotoxicity, demyelination, Elite Womens Chris Canty jersey reduced neurotrophic support, metabolic impairment, and altered intracellular processes. Here we survey available data concerning the role of autoreactive immunoglobulins in neurotoxicity. A generally accepted view of MS pathogenesis Mens Dennis Pitta jersey has linked the disease process to myelin specific, CD4 T lymphocytes which, upon activation by unknown factors, migrate through the blood barrier (BBB), engage CNS related antigenic peptides presented by Mens Dennis Pitta jersey Authenitc Mens Dennis Pitta jersey antigen presenting cells, clonally expand, and exert cytotoxic attacks on oligodendrocytes and myelin. This hypothesis has been largely driven by observations from the experimental autoimmune encephalomyelitis (EAE) model that represents a demyelinating CNS disorder mediated by myelin specific CD4 T cells.2, 3However, recent histological analyses4 and in vivo studies by magnetic resonance imaging (MRI) and spectroscopy (MRS)5, 6 emphasize that neurodegeneration develops along with Authenitc Blue Eugene Monroe jersey inflammatory demyelination. The pathology affects the entire brain, but with different distributions of inflammation, demyelination, and neurodegeneration in the white and gray matter.7 The neuroaxonal loss is likely to be secondary to inflammation and demyelination, but it begins in the earliest stages of the disease and progresses even after the decline of inflammation. Most importantly, neuroaxonal loss represents the major pathological correlate of clinical disability.5 Further evidence to support the importance of neurodegeneration in MS Kids Dennis Pitta jersey is obtained from clinical data showing only a partial success of the available disease modifying drugs (interferons, glatiramer acetate, monoclonal antibodies to antigenic determinants expressed on T lymphocytes), which impede activation and migration of inflammatory cells via the BBB, but have no direct effect on the degenerative processes in CNS.8The exploration of neurodegeneration in MS received high priority in the last few years. The data establish that this is a multifactorial process involving loss of myelin protection, immune mediated histotoxicity, decreased trophic support, mitochondrial damage, metabolic changes, and altered signaling.9, 10, 11, 12 We recently reviewed our and others’ published works concerning the involvement of mitochondrial mechanisms in neurodegeneration associated with inflammation.13, 14, 15 As an extension of surveys on neuroaxonal loss related to inflammatory demyelination, the present paper focuses on the involvement of humoral immune factors Youth Chris Canty jersey (Table 1). The available information allows us to generate a preliminary concept of immune mediated neuronal dysfunction and loss, and to highlight potential pathways amenable to therapeutic interventions (Figure 1; Tables 2, 3 and 4). This figure depicts the thus far identified CNS antigens targeted by humoral autoimmunity in inflammatory demyelination. Signs of autoimmunity are lacking in type III and IV lesions which appear as variants of a primary oligodendrocytopathy. However, humoral autoimmunity is not only involved in certain forms of demyelination, but also instrumental in Elite Womens Brandon Williams jersey the process of neurodegeneration but with thus far unknown relative destructivity in various disease subtypes.Immunologic and Molecular DataThe literature is markedly weighted towards characterization of the cellular arm of autoimmunity, but new data also support that B cells and humoral immunity play important roles in MS. The B cell lineage is represented by B lymphocytes (CD19 CD138 plasma blasts (CD19 CD138 and plasma cells (CD19 CD138 for brevity, altogether B cells) in CNS and cerebrospinal fluid (CSF). Most of these cells express memory (CD27 phenotypes in MS. Therapeutic observations support that B cells may both directly and indirectly contribute to the development of MS. Removal of immunoglobulins from the peripheral blood by plasmapheresis appears to be beneficial in the subgroup of patients with type II lesions59 and depletion of CD20 B cells by rituximab results in a significant reduction in the number of enhancing MRI lesions. The latter intervention, however, does not exert its beneficial effects by directly affecting the immunoglobulin pool, but by depleting memory B cells and altering antigen presentation, T cell activation, or T cell recruitment into the CNS.60Molecular data also support the involvement of B lymphocytes and their products in MS. Intrathecal production of immunoglobulins with an oligoclonal electrophoretic distribution pattern Elite Kids Brandon Williams jersey is a hallmark of the disease. These B cell clones exhibit complex molecular characteristics and intraclonal diversity.Activation of B CellsWhat drives B cell activation and clonal expansion is not fully understood. Epstein virus (EBV), a B lymphotropic microorganism, has been implicated in the development of the disease by epidemiological, immune serological, and histological studies.64, 65 MS patients have intracerebral accumulation of EBV infected B cells and plasma blasts, mostly in ectopic B cell follicles,39 and a cross reactivity of the anti EBV specific cells with CNS antigens has been noted.64, 65 Other mechanisms leading to autoimmune B cell activation may be initiated by CD4 T helper type 2 (TH2) lymphocytes and their soluble inflammatory products (eg interleukine Elite Kids Dennis Pitta jersey 4, 5, and 13),66 followed by an antigen specific expansion of clones either in the peripheral circulation or in the damaged CNS tissue, where intracellular proteins are released. Bystander activation describes a non antigen specific activation of T or B cells usually mediated by soluble inflammatory products of nearby immune cells.Anti Myelin AntibodiesImmunoglobulins produced by activated B cells in the CNS and CSF target numerous self antigens including components of the CNS myelin such as myelin basic protein, proteolipid protein, myelin associated glycoprotein, and myelin oligodendrocyte glycoprotein.67, 68 A great number of papers discusses the involvement of myelin specific antibodies in the development of demyelination and disease progression.69, 70 Pros and cons for the primary pathogenic significance or the reactive nature of anti myelin specific B cells have been debated.71, 72 The use of some of these antibodies as biomarkers to support the diagnosis or to monitor disease activity and course also has been proposed, but not uniformly accepted.73, 74Anti Neuronal AntibodiesAutoantibodies that target neuronal molecules and potentially exert histotoxicity have been less scrutinized. Nevertheless, growing data reveal that these antigen interactions play important roles in Elite Black Brandon Williams jersey a number of neuroinflammatory and Elite Eugene Monroe jersey neurodegenerative conditions. In contrast to Womens Eugene Monroe jersey the usual scenario of a T lymphocyte driven autoimmunity and tissue damage, the humoral immune system appears to be more successful in breaking Elite Mens Crockett Gillmore jersey anti neuronal tolerance than the cellular system, and has greater pathogenic significance.43 This survey presents information that supports the involvement of the humoral immune response in MS related neurodegeneration.Top of pageANTI NEURONAL ANTIBODIES IN MSAntibodies Targeting Neuronal Cell Surface MoleculesNeuronal cell surface antigens Molecules in the surface membrane of myelinated axons are normally hidden from the immune system, and only become exposed after demyelination when they become antigenic and induce the production of neuron specific antibodies. IgG and IgM antibodies binding to the surface of a neuronal cell line were found in 70 of sera from patients with secondary progressive (SP) MS and in 25 of sera from patients with relapsing remitting (RR) MS.42 This finding may indicate the spreading of autoimmunity to neuronal antigens as a consequence of CNS tissue damage, and the expansion of pathology from moderate to marked neuroaxonal loss associated with a transition from RR to SP MS course.Axolemma Elite Black Brandon Williams jersey enriched fractions Antibodies to axolemma enriched fractions (AEF) of the CNS are also present in CSF and sera of MS patients.16 These antibodies damage neurites and prevent neuronal outgrowth in vitro. The production of anti axolemma and anti myelin IgGs appears to be independent. Based on these observations, the use of anti axolemma IgGs as markers of axonal damage was proposed.55Neurofascin One of the targets in antibody mediated axonal injury is a cell adhesion molecule neurofascin. The 186 neuron specific isoform of neurofascin (NF186) is required for the clustering of voltage gated Na channels at the nodes of Ranvier. The 155 glial specific isoform (NF155) is required for the proper assembly of paranodal junction, an important site of interactions between the myelin and axon. Early changes in the distribution of NF155 were observed in MS lesions preceding demyelination.44 Maier et al45 showed that the NF155 levels were reduced and a 40 NF155 fragment increased in plaques, suggesting that NF155 is subject to protein degradation in the lesions.Levels of antibodies to NF155 and NF186 were significantly higher in sera of patients with chronic progressive forms of MS compared to that of Elite Kids Eugene Monroe jersey patients with other inflammatory neurological diseases.17 In vitro studies showed that antibodies to neurofascin inhibit axonal conduction. In vivo experiments revealed that antibodies to neurofascin and complement can selectively target nodes of Ranvier, cause axonal injury, and trigger disease Chris Canty jersey exacerbation in EAE. Mathey et al17 also showed that NF155 specific antibodies cross react with NF186 transfected cells. The recognition of NF186 at the nodes of Ranvier by these antibodies may initiate axonal injury and accelerate disease progression. Neurofascin specific antibodies can also inhibit remyelination by binding to NF155 expressed on the surface of oligodendrocytes.Gangliosides Another group of neuronal antigens includes the gangliosides, which are glycolipids with sialic residues in the outer layer of cell membranes. Gangliosides are particularly enriched in the membranes of neuron. To generate antibody responses, gangliosides do not require major histocompatibility complex (MHC) molecules and T cell Elite Youth Chris Canty jersey help.75 Although it is unclear whether anti ganglioside antibodies can cause or result from axonal damage,18 they may certainly serve as a marker of this process. Experimental data reveal that anti ganglioside antibodies can disrupt the BBB,19 create neuromuscular block by binding to neuronal gangliosides in the neuromuscular junction,56 and inhibit axonal regeneration after peripheral nerve injury in mice.20 Complexes of anti ganglioside antibodies and complement destroy Schwann cells and myelin membranes in demyelinating neuropathies, and contribute to axonal degeneration in acute motor axonal neuropathy.41 Increased levels of anti GM3 (monosialo ganglioside) antibodies can be found in sera of a great proportion of patients with progressive forms of MS (56.3 in primary progressive (PP) MS and 42.9 in SP MS vs 2.9 in RR MS and 14.6 in OND).18 Anti GD2 (disialo ganglioside) like IgM autoantibodies were detected in sera of 30 of MS patients, and a positive correlation of anti GD2 like IgM reactivity with neurological disability was observed.21 The increased Authenitc Brandon Williams jersey prevalence of GD2 specific IgM antibodies in SP MS (47.8 compared to RR MS (24.2 and PP MS (26.7 also suggests the involvement of these antibodies in inflammation induced neurodegeneration.In summary, these data suggest that antibodies specific to neuronal cell Elite Black Eugene Monroe jersey surface molecules are produced during demyelination and may themselves contribute to axonal injury in MS. These antibodies can activate complement and exert cytotoxicity, provide binding sites for the Fc receptors on macrophages and microglial cells, interrupt axon interaction, inhibit axonal conduction and outgrowth, disrupt the BBB, and alter oligodendrocyte functioning. Correlation of the antibody titers with the severity of disability offers an opportunity of using these neuronal cell surface antibodies as biomarkers.Antibodies to Cytoskeletal ProteinsNeurofilaments Neurofilaments are a group of cytoskeletal proteins expressed in neuronal cells and axons. A variety of neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and dementia with Lewy bodies are characterized by accumulation of NF proteins signifying abnormalities in the axonal transport and an impending neuronal loss.76, 77Antibodies to axonal cytoskeletal proteins may be markers of axonal damage, as well as important contributors to neurodegeneration and clinical disability in MS. CSF levels of antibodies against the light subunit of neurofilaments (NFL) correlate with the disease duration, clinical disability, IgG index, and the degree of cerebral atrophy measured by MRI.22, 23 Although elevated levels of NFL specific antibodies are present in sera of patients with PP MS,24 these antibodies are also increased in sera of patients with OND.22Tamara Vyshkina1 and Bernadette Kalman1,2Received Womens Crockett Gillmore jersey 12 March 2008; Chris Canty jersey Revised 21 April 2008; Accepted 25 April 2008; Published online 2 June 2008.Top of pageAbstractNeurodegeneration develops in association with inflammation and demyelination in multiple sclerosis. Available data suggest that the progressive neuroaxonal loss begins in the earliest stages of the disease and underlies the accumulation of clinical disability. The loss of neurons and their processes is driven by a complex molecular mechanism involving cellular and humoral immune histotoxicity, demyelination, reduced neurotrophic support, metabolic impairment, and altered intracellular processes. Here we survey available data concerning the role of autoreactive immunoglobulins in neurotoxicity. A generally accepted view of MS pathogenesis has linked the disease process to myelin specific, CD4 T lymphocytes which, upon activation by unknown factors, migrate through the blood barrier (BBB), engage CNS related antigenic peptides presented by antigen presenting cells, clonally expand, and exert cytotoxic attacks on oligodendrocytes and myelin. This hypothesis has been largely driven by observations from the experimental autoimmune encephalomyelitis (EAE) model Youth Crockett Gillmore jersey that represents a demyelinating CNS disorder mediated by myelin specific CD4 T cells.2, 3However, recent histological analyses4 and in vivo studies by magnetic resonance imaging (MRI) and spectroscopy (MRS)5, 6 emphasize that neurodegeneration develops along with inflammatory demyelination. The pathology affects the entire brain, but with different distributions of inflammation, demyelination, and neurodegeneration in the white and gray matter.7 The neuroaxonal loss is likely to be secondary to inflammation and demyelination, but it begins in the earliest stages of the Elite Black Brandon Williams jersey disease and progresses even after the decline of inflammation. Most importantly, neuroaxonal loss represents the major pathological correlate of clinical disability.5 Further evidence to support the importance of neurodegeneration in MS is obtained from clinical data showing only a partial success of the available disease modifying drugs (interferons, glatiramer acetate, monoclonal antibodies to antigenic determinants expressed on T lymphocytes), which impede activation and migration of inflammatory cells via the BBB, but have no direct effect on the degenerative processes in CNS.8The exploration of neurodegeneration in MS received high priority in the last few years. The data establish Authenitc Kids Brandon Williams jersey that this is a multifactorial process involving loss of myelin protection, immune mediated histotoxicity, decreased trophic support, mitochondrial damage, metabolic changes, and altered signaling.9, 10, 11, 12 We recently reviewed our and others’ published works concerning the involvement of mitochondrial mechanisms in neurodegeneration associated with inflammation.13, 14, 15 As an extension of surveys on neuroaxonal loss related to inflammatory demyelination, the present paper focuses on the involvement of humoral immune factors (Table 1). The available information allows us to generate a preliminary concept of immune mediated neuronal dysfunction and loss, and to highlight potential pathways amenable to therapeutic interventions (Figure 1; Tables 2, 3 and 4). Elite Mens Brandon Williams jersey This figure depicts the thus far identified CNS antigens targeted by humoral autoimmunity in inflammatory demyelination. Signs of autoimmunity are lacking in type III and IV lesions which appear as variants of a primary oligodendrocytopathy. However, humoral autoimmunity is not only involved in certain forms of demyelination, but also instrumental in the process of neurodegeneration but with thus far unknown relative destructivity in various disease subtypes.Immunologic and Molecular DataThe literature is markedly weighted towards characterization of the cellular arm of autoimmunity, but new data also support that B cells and humoral immunity play important roles Crockett Gillmore jersey in MS. The B cell lineage is represented by B lymphocytes (CD19 CD138 plasma blasts (CD19 CD138 and plasma cells (CD19 CD138 for brevity, altogether B cells) in CNS and cerebrospinal fluid (CSF). Most of these cells express memory (CD27 phenotypes in MS. Therapeutic observations support that B cells may both directly and indirectly contribute to the development of Elite Black Chris Canty jersey MS. Removal of immunoglobulins from the peripheral blood by plasmapheresis appears to be beneficial in the subgroup of patients with type II lesions59 and depletion of CD20 B cells by rituximab results in a significant reduction in the number of enhancing MRI lesions. The latter intervention, however, does not exert its beneficial effects by directly affecting the immunoglobulin pool, but by depleting memory B cells and altering antigen presentation, T cell activation, or T cell recruitment into the CNS.60Molecular data also support the Youth Chris Canty jersey involvement of B lymphocytes and their products in MS. Intrathecal production of immunoglobulins with an oligoclonal electrophoretic distribution pattern is a hallmark of the disease. These B cell clones exhibit complex molecular characteristics and intraclonal diversity.Activation of B CellsWhat drives B cell activation and clonal expansion is not fully understood. Epstein virus (EBV), a B lymphotropic microorganism, has been implicated in the development of the disease by epidemiological, immune serological, and histological studies.64, 65 MS patients have intracerebral accumulation of EBV infected B cells and plasma blasts, mostly in ectopic B cell follicles,39 and a cross reactivity of the anti EBV specific cells with CNS antigens has been noted.64, 65 Other mechanisms leading to autoimmune B cell activation may be initiated by CD4 T helper type 2 (TH2) lymphocytes and their soluble inflammatory products (eg interleukine 4, 5, Mens Jeromy Miles jersey and 13),66 followed by an antigen specific expansion of clones either in the peripheral circulation or in the damaged CNS tissue, where intracellular proteins are released. Bystander activation describes a non antigen specific activation of T or B cells usually mediated by soluble inflammatory products of nearby immune cells.Anti Myelin AntibodiesImmunoglobulins produced by activated B cells in the CNS and CSF target numerous self antigens including components of the CNS myelin such as myelin basic protein, proteolipid protein, myelin associated glycoprotein, and myelin oligodendrocyte glycoprotein.67, 68 A great number of papers discusses the involvement of myelin specific antibodies in the development of demyelination and disease progression.69, 70 Pros and cons for the primary pathogenic significance or the reactive nature of anti myelin specific B cells have been debated.71, 72 The use of some of these antibodies as biomarkers to support the diagnosis Elite Kids Eugene Monroe jersey or to monitor disease activity and course also has been Authenitc Youth Crockett Gillmore jersey proposed, but not uniformly accepted.73, 74Anti Neuronal AntibodiesAutoantibodies that target neuronal molecules and potentially exert histotoxicity have been less scrutinized. Nevertheless, growing Elite Womens Eugene Monroe jersey data reveal that these antigen interactions play important roles in a number of Elite Crockett Gillmore jersey neuroinflammatory and neurodegenerative conditions. In contrast to the usual scenario of a T lymphocyte driven autoimmunity and tissue damage, the humoral immune system appears to be more successful in breaking anti neuronal tolerance than the cellular system, and has greater pathogenic significance.43 This survey presents information that supports the involvement of the humoral immune response in MS related neurodegeneration.Top of pageANTI NEURONAL ANTIBODIES IN MSAntibodies Targeting Neuronal Cell Surface MoleculesNeuronal cell surface Chris Canty jersey antigens Molecules in the surface membrane of myelinated axons are normally hidden from the immune system, and only become exposed after demyelination when they become antigenic and induce the production of neuron specific antibodies. IgG and IgM antibodies binding to the surface of a neuronal cell line were found in 70 of sera from patients with secondary progressive (SP) MS and in 25 of sera from patients with relapsing remitting (RR) MS.42 This finding may indicate the spreading of autoimmunity Youth Eugene Monroe jersey to neuronal antigens as a consequence of CNS tissue damage, and the expansion of pathology Authenitc Blue Brandon Williams jersey from moderate to marked neuroaxonal loss associated with a transition from RR to SP MS course.Axolemma enriched fractions Antibodies to axolemma enriched fractions (AEF) of the CNS are also present in CSF and sera of MS patients.16 These antibodies damage neurites and prevent neuronal outgrowth in vitro. The production of anti axolemma and anti myelin IgGs appears to be independent. Based on these observations, the use of anti axolemma IgGs as markers of axonal damage was proposed.55Neurofascin One of the targets in antibody mediated axonal injury is a cell adhesion molecule neurofascin. The 186 neuron specific isoform of neurofascin (NF186) is required for the clustering of voltage gated Na channels at the nodes of Ranvier. The 155 glial specific isoform (NF155) is required for the proper assembly of paranodal junction, an important site of interactions between the myelin and axon. Early changes in Authenitc Kids Chris Canty jersey the distribution of NF155 were observed in MS lesions preceding demyelination.44 Maier et al45 showed that the NF155 levels were reduced and a 40 NF155 fragment increased in plaques, suggesting that NF155 is subject to protein degradation in the lesions.Levels of antibodies to NF155 and NF186 were significantly higher in sera of patients with chronic progressive forms of MS compared to that of patients with other inflammatory neurological diseases.17 In vitro studies showed that antibodies to neurofascin inhibit axonal conduction. In vivo experiments revealed Authenitc Mens Eugene Monroe jersey that antibodies to neurofascin and complement can selectively target nodes of Ranvier, cause axonal injury, and trigger disease exacerbation in EAE. Mathey et al17 also showed that NF155 specific antibodies cross react with NF186 transfected cells. The recognition of NF186 at the nodes of Ranvier by these antibodies may initiate axonal injury and accelerate disease progression. Neurofascin specific antibodies can also inhibit remyelination by binding to NF155 expressed on the surface of oligodendrocytes.Gangliosides Another group of neuronal antigens includes the gangliosides, which are glycolipids with sialic residues in the outer layer of cell membranes. Gangliosides are particularly enriched in the membranes of neuron. To generate antibody responses, gangliosides do not require major histocompatibility complex (MHC) molecules and T cell help.75 Although it is unclear whether anti ganglioside antibodies can cause or result from axonal damage,18 they may certainly serve as a marker of this process. Experimental data reveal that anti ganglioside antibodies can disrupt the BBB,19 create neuromuscular block by binding to neuronal gangliosides in the neuromuscular junction,56 and inhibit axonal regeneration after peripheral nerve injury in mice.20 Complexes of anti ganglioside antibodies and complement destroy Schwann cells and myelin membranes in demyelinating neuropathies, and contribute to axonal degeneration in acute motor axonal neuropathy.41 Increased levels of anti GM3 (monosialo ganglioside) antibodies can be found in sera of a great proportion of patients with progressive forms of MS (56.3 in primary progressive (PP) MS and 42.9 in SP MS vs 2.9 in RR MS and 14.6 in OND).18 Anti GD2 (disialo ganglioside) like IgM autoantibodies were detected in sera of 30 of MS patients, and a positive correlation of anti GD2 like IgM reactivity with neurological disability was observed.21 The increased prevalence of GD2 specific IgM antibodies in SP MS (47.8 compared to RR MS (24.2 and PP MS (26.7 also suggests the involvement of these antibodies in inflammation induced neurodegeneration.In summary, these data suggest that antibodies specific to neuronal cell surface molecules are produced during demyelination and may themselves contribute to axonal injury in MS. These antibodies can activate complement and exert cytotoxicity, provide binding sites for the Fc receptors on macrophages and microglial cells, interrupt axon interaction, inhibit axonal conduction and outgrowth, disrupt the BBB, and alter oligodendrocyte functioning. Correlation of the antibody titers with the severity of disability offers an opportunity of using these neuronal cell surface antibodies as biomarkers.Antibodies to Cytoskeletal ProteinsNeurofilaments Neurofilaments are a group of cytoskeletal proteins expressed in neuronal cells and axons. A variety of neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and Authenitc Blue Chris Canty jersey dementia with Lewy bodies are characterized by accumulation of NF proteins signifying abnormalities in the axonal transport and an impending neuronal loss.76, 77Antibodies to axonal cytoskeletal proteins may be markers of axonal damage, as well as important contributors to neurodegeneration and clinical disability in MS. CSF levels of antibodies against the light subunit of neurofilaments (NFL) correlate with the disease duration, clinical disability, IgG index, and the degree of cerebral atrophy measured by MRI.22, 23 Although elevated levels of NFL specific antibodies are present in sera of patients with PP MS,24 these antibodies are also increased in sera of patients with OND.22

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