Abstract

BackgroundWe could previously identify components of both the innate and the adaptive immune system as disease modifiers in the pathogenesis of models for Charcot-Marie-Tooth (CMT) neuropathies type 1B and 1X. As part of the adaptive immune system, here we investigated the role of antibodies in a model for CMT1B.MethodsAntibodies were localized and characterized in peripheral nerves of the CMT1B model by immunohistochemistry and Western blot analysis. Experimental ablation of antibodies was performed by cross breeding the CMT1B models with mutants deficient in B-lymphocytes (JHD−/− mutants). Ameliorated demyelination by antibody deficiency was reverted by intravenous injection of mouse IgG fractions. Histopathological analysis was performed by immunocytochemistry and light and quantitative electron microscopy.ResultsWe demonstrate that in peripheral nerves of a mouse model for CMT1B, endogenous antibodies strongly decorate endoneurial tubes of peripheral nerves. These antibodies comprise IgG and IgM subtypes and are preferentially, but not exclusively, associated with nerve fiber aspects nearby the nodes of Ranvier. In the absence of antibodies, the early demyelinating phenotype is substantially ameliorated. Reverting the neuropathy by reconstitution with murine IgG fractions identified accumulating antibodies as potentially pathogenic at this early stage of disease.ConclusionsOur study demonstrates that in a mouse model for CMT1B, endogenous antibodies contribute to early macrophage-mediated demyelination and disease progression. Thus, both the innate and adaptive immune system are mutually interconnected in a genetic model for demyelination. Since in Wallerian degeneration antibodies have also been shown to be involved in myelin phagocytosis, our study supports our view that inherited demyelination and Wallerian degeneration share common mechanisms, which are detrimental when activated under nonlesion conditions.

Highlights

  • We could previously identify components of both the innate and the adaptive immune system as disease modifiers in the pathogenesis of models for Charcot-Marie-Tooth (CMT) neuropathies type 1B and 1X

  • While in models for CMT1A, macrophages were identified as the only inflammationrelated disease modulators [6,7], disease outcome in models for CMT1B and CMT1X is influenced by components of both the innate [8,9,10,11,12] and the adaptive immune system [13,14,15]

  • Klein et al Journal of Neuroinflammation (2015) 12:49 to putative molecular similarities between Wallerian degeneration and pathogenesis of CMT [5], we investigated the role of antibodies in a demyelinating model for CMT1B

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Summary

Introduction

We could previously identify components of both the innate and the adaptive immune system as disease modifiers in the pathogenesis of models for Charcot-Marie-Tooth (CMT) neuropathies type 1B and 1X. Charcot-Marie-Tooth (CMT) type 1 disorders comprise a genetically heterogeneous group of inherited peripheral neuropathies that are characterized by length-dependent axonal degeneration, muscle atrophy, and sensory dysfunction, substantially reducing quality of life [1,2]. Klein et al Journal of Neuroinflammation (2015) 12:49 to putative molecular similarities between Wallerian degeneration and pathogenesis of CMT [5], we investigated the role of antibodies in a demyelinating model for CMT1B. We demonstrate here that endoneurial tubes of peripheral nerves of P0het myelin mutant mice are decorated with endogenous antibodies. Our study identifies endogenous antibodies as a link in the interaction between the innate and adaptive immune system during early pathogenesis in a model for CMT1B

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