title: Endogenous antibodies contribute to macrophage-mediated demyelination in a mouse model for CMT1B.
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.
authors: Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Josef-Schneider-Str 11, D-97080, Würzburg, Germany. Klein_D2@ukw.de.
authors: Dennis
authors: D
authors: Klein
authors: Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Josef-Schneider-Str 11, D-97080, Würzburg, Germany. Groh_J@ukw.de.
authors: Janos
authors: J
authors: Groh
authors: Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Josef-Schneider-Str 11, D-97080, Würzburg, Germany. Weishaupt_A@ukw.de.
authors: Andreas
authors: A
authors: Weishaupt
authors: Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Josef-Schneider-Str 11, D-97080, Würzburg, Germany. rudolf.martini@mail.uni-wuerzburg.de.
authors: Rudolf
authors: R
authors: Martini
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000150:complications* / Q000235:genetics; D003711:Demyelinating Diseases / Q000209:etiology* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018993:Myelin P0 Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D020426:Sciatic Neuropathy / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000906:Antibodies; D000943:Antigens, Differentiation; D018398:Homeodomain Proteins; D018993:Myelin P0 Protein; C036763:monocyte-macrophage differentiation antigen; C064658:RAG-1 protein