Abstract
BackgroundNeurodegeneration is believed to be the primary cause of permanent, long-term disability in patients with multiple sclerosis. The cause of neurodegeneration in multiple sclerosis appears to be multifactorial. One mechanism that has been implicated in the pathogenesis of neurodegeneration in multiple sclerosis is the targeting of neuronal and axonal antigens by autoantibodies. Multiple sclerosis patients develop antibodies to the RNA-binding protein, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), which is enriched in neurons. We hypothesized that anti-hnRNP A1 antibodies would contribute to neurodegeneration in an animal model of multiple sclerosis.MethodsFollowing induction of experimental autoimmune encephalomyelitis (EAE) by direct immunization with myelin oligodendrocyte glycoprotein, mice were injected with anti-hnRNP A1 or control antibodies. Animals were examined clinically, and the central nervous system (CNS) tissues were tested for neurodegeneration with Fluoro-Jade C, a marker of degenerating neural elements.ResultsInjection of anti-hnRNP A1 antibodies in mice with EAE worsened clinical disease, altered the clinical disease phenotype, and caused neurodegeneration preferentially in the ventral spinocerebellar tract and deep white matter of the cerebellum in the CNS. Neurodegeneration in mice injected with hnRNP A1-M9 antibodies compared to control groups was consistent with “dying back” axonal degeneration.ConclusionsThese data suggest that antibodies to the RNA-binding protein hnRNP A1 contribute to neurodegeneration in immune-mediated disease of the CNS.
Highlights
Neurodegeneration is believed to be the primary cause of permanent, long-term disability in patients with multiple sclerosis
Upon the first clinical signs of EAE, the mice were injected with phosphate-buffered saline (PBS), anti-mouse IgG2b, or mouse anti-hnRNP heterogeneous nuclear ribonucleoprotein A1 (A1)-M9 antibodies (100 μg ip on days 0, 2, and 4, for a total of three injections) (Fig. 1)
Anti-hnRNP A1-M9 antibodies cause increased levels of neurodegeneration of specific central nervous system (CNS) pathways in EAE After observing that anti-hnRNP A1-M9 antibodies worsened EAE, we hypothesized that the augmented clinical progression might be related to changes in neurodegeneration in the CNS
Summary
Neurodegeneration is believed to be the primary cause of permanent, long-term disability in patients with multiple sclerosis. One mechanism that has been implicated in the pathogenesis of neurodegeneration in multiple sclerosis is the targeting of neuronal and axonal antigens by autoantibodies. We hypothesized that anti-hnRNP A1 antibodies would contribute to neurodegeneration in an animal model of multiple sclerosis. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, data indicate that, as in MS, neuronal and axonal damage are present throughout the course of the disease and contribute to the neurologic disability [13,14,15]. MS patients were found to make antibodies to neurofascin [24, 25], a protein with an isoform present on the axons at the nodes of Ranvier [24, 25]. Following induction of EAE with myelin oligodendrocyte glycoprotein (MOG)-specific T cells, the addition of anti-neurofascin antibodies augmented disease [24, 25]
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