Further, microarray analyses of neurons exposed to anti-hnRNP A1 antibodies revealed novel pathways of neurodegeneration related to alterations of RNA levels of the spinal paraplegia genes (SPGs)

Hydroxysteroid Dehydrogenase, 11??- 0 Comments

Further, microarray analyses of neurons exposed to anti-hnRNP A1 antibodies revealed novel pathways of neurodegeneration related to alterations of RNA levels of the spinal paraplegia genes (SPGs). cell lines, suggesting the autoantibodies are pathogenic. Further, microarray analyses of neurons exposed to anti-hnRNP A1 antibodies revealed novel pathways of neurodegeneration related to alterations of RNA levels of the spinal paraplegia genes (SPGs). Mutations in SPGs cause hereditary spastic paraparesis, genetic disorders clinically indistinguishable from progressive MS and HAM/TSP. Thus, there is a strong association between involvement of SPGs in neurodegeneration and the clinical phenotype of progressive MS and HAM/TSP patients, who commonly develop spastic paraparesis. Taken together, these data begin to clarify mechanisms of neurodegeneration related to the clinical presentation of patients with chronic immune-mediated neurological disease of the central nervous system, which will give AZ304 insights into the design of AZ304 novel therapies to treat these neurological diseases. provirus and RNA were localized to infiltrating T cells in the spinal cord.67,68 There is little evidence of direct infection of neural elements with HTLV-1. Thus, data indicate that immune-mediated mechanisms contribute to the pathogenesis of HAM/TSP.12,13,20,22,24,69C73 For example, HAM/TSP patients make immune responses to a number of viral targets including HTLV-1 that separates them from control populations.74C77 Immunologically, HAM/TSP patients develop CD8+, human leukocyte antigen (HLA)-2-restricted cytotoxic T lymphocytes (CTLs) specific for and CD4+ responses to both and that are thought to contribute to disease.74,75,78 In contrast, other studies suggest that C spastin), (paraplegin), and (spartin), have all been shown to contribute to axonal transport.27,28,99C102 In addition to these mechanisms, recent studies have implicated RNA-binding proteins (RBPs) and their function in RNA metabolism (ie, transport, stability, translation) as major contributors to abnormal neuronal function and neurodegeneration in amyotrophic lateral sclerosis, spinal muscle atrophy, and dementia.103,104 For example, the RBP TAR DNA-binding AZ304 protein 43 has been identified as a major contributor to amyotrophic lateral sclerosis and frontotemporal dementia.105,106 Also, RNA metabolism related to fragile X mental retardation protein appears to contribute to the pathogenesis of fragile X syndrome and fragile X syndrome-associated tremor/ataxia.103 Further, patients with paraneoplastic neurologic syndromes develop antibodies to RBPs, such as Hu and Nova.103,107,108 Taken together, these data show that neurodegeneration in MS involves mechanisms that are also present in other neurodegenerative diseases. Antibodies as contributors to neurodegeneration and the pathogenesis of MS In addition to T cells, recent studies have emphasized the role of humoral autoimmunity in the pathogenesis of MS.47,109,110 Clinically, intrathecal IgG and oligoclonal bands are a hallmark of MS.109,110 Some types of MS show Ig and complement deposition in MS lesions, and some MS patients exhibit a therapeutic response to plasma exchange or B-cell depletion with anti-CD20 antibodies. 111C117 The humoral immune response may be particularly important when studying neurodegeneration.1,4,37C41,118 For example, patients with progressive disease are more likely to have B-cell follicle-like structures in the cerebral meninges.56,57,110,117 IgG-containing plasma cells are found in the meninges and throughout the brain in MS patients, and persist in progressive forms of MS when T cells and B cells diminish to control levels.48,117 Importantly, studies also show that antibodies Mouse monoclonal to CD3.4AT3 reacts with CD3, a 20-26 kDa molecule, which is expressed on all mature T lymphocytes (approximately 60-80% of normal human peripheral blood lymphocytes), NK-T cells and some thymocytes. CD3 associated with the T-cell receptor a/b or g/d dimer also plays a role in T-cell activation and signal transduction during antigen recognition to neurons and axons contribute to the pathogenesis of neurodegeneration in MS.119,120 In one study, MS patients were found to make antibodies to neurofascin.119,120 The autoantibodies reacted to both neurofascin 186 (a neuronal protein located on axons at the AZ304 nodes of Ranvier) and neurofascin 155, an oligodendrocyte protein.119,120 Application of these antibodies to hippocampal slice cultures inhibited axonal conduction.120 Following induction of experimental allergic encephalomyelitis with myelin oligodendrocyte glycoprotein-specific T cells, the addition of antineurofascin antibodies augmented AZ304 disease.120 The antibodies bound to the nodes of Ranvier, resulting in complement deposition.