Immunization with neurofilament light protein induces spastic paresis and axonal degeneration in Biozzi ABH mice

J Neuropathol Exp Neurol. 2007 Apr;66(4):295-304. doi: 10.1097/nen.0b013e318040ad5c.

Abstract

Axonal damage is the major cause of irreversible neurologic disability in patients with multiple sclerosis. Although axonal damage correlates with antibodies against neurofilament light (NF-L) protein, a major component of the axonal cytoskeleton, the possible pathogenic role of autoimmunity to axonal antigens such as NF-L has so far been ignored. Here we show that Biozzi ABH mice immunized with NF-L protein develop neurologic disease characterized by spastic paresis and paralysis concomitant with axonal degeneration and inflammation primarily in the dorsal column of the spinal cord. The inflammatory central nervous system lesions were dominated by F4/80+ macrophages/microglia and relatively low numbers of CD4+ and CD8+ T-cells. In splenocyte cultures, proliferation to NF-L was observed in CD4+ T-cells accompanied by the production of the proinflammatory cytokine interferon-gamma. Elevated levels of circulating antibodies recognizing recombinant mouse NF-L were present in the serum, and immunoglobulin deposits were observed within axons in spinal cord lesions of mice exhibiting clinical disease. These data provide evidence that autoimmunity to NF-L protein induces axonal degeneration and clinical neurologic disease in mice, indicating that autoimmunity to axonal antigens, as described in multiple sclerosis, may be pathogenic rather than acting merely as a surrogate marker for axonal degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / blood
  • Axons / pathology*
  • Axons / ultrastructure
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Cell Proliferation
  • Cytokines / metabolism
  • Female
  • Flow Cytometry / methods
  • Immunization / methods*
  • Male
  • Mice
  • Mice, Biozzi
  • Microscopy, Electron, Transmission / methods
  • Muscle Spasticity / etiology*
  • Muscle Spasticity / immunology
  • Muscle Spasticity / pathology
  • Muscle Spasticity / physiopathology
  • Myelin Proteins
  • Myelin-Associated Glycoprotein / immunology
  • Myelin-Oligodendrocyte Glycoprotein
  • Nervous System Diseases / chemically induced*
  • Nervous System Diseases / immunology
  • Nervous System Diseases / pathology*
  • Neurofilament Proteins* / immunology
  • Sciatic Nerve / immunology
  • Sciatic Nerve / metabolism
  • Sciatic Nerve / pathology
  • Sciatic Nerve / ultrastructure
  • Spinal Cord / immunology
  • Spinal Cord / metabolism
  • Spinal Cord / pathology

Substances

  • Antibodies
  • Cytokines
  • Mog protein, mouse
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Myelin-Oligodendrocyte Glycoprotein
  • Neurofilament Proteins
  • neurofilament protein L