Endogenous Antibodies Contribute to Macrophage-mediated Demyelination in a Mouse Model for CMT1B

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2015 Apr 17

PMID 25879857

Citations 5

Authors

Dennis Klein

Janos Groh

Andreas Weishaupt

Rudolf Martini

Affiliations

Soon will be listed here.

Abstract

Background: 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. As part of the adaptive immune system, here we investigated the role of antibodies in a model for CMT1B.

Methods: Antibodies 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.

Results: We 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.

Conclusions: Our 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.

Citing Articles

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Plasma membrane abundance dictates phagocytic capacity and functional cross-talk in myeloid cells.

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Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies.

Stavrou M, Sargiannidou I, Georgiou E, Kagiava A, Kleopa K Int J Mol Sci. 2021; 22(11).

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Phagocytosis by Peripheral Glia: Importance for Nervous System Functions and Implications in Injury and Disease.

Nazareth L, St John J, Murtaza M, Ekberg J Front Cell Dev Biol. 2021; 9:660259.

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Neuroinflammation in the peripheral nerve: Cause, modulator, or bystander in peripheral neuropathies?.

Martini R, Willison H Glia. 2015; 64(4):475-86.

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