T cell-activation in neuromyelitis optica lesions plays a role in their formation

Acta Neuropathol Commun. 2013 Dec 24;1:85. doi: 10.1186/2051-5960-1-85.

Abstract

Background: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS), which is characterized by the presence of pathogenic serum autoantibodies against aquaporin 4 (AQP4) in the vast majority of patients. The contribution of T cells to the formation of astrocyte destructive lesions is currently unclear. However, active human NMO lesions contain CD4+ T-lymphocytes expressing the activation marker Ox40, and the expression is more profound compared to that seen in MS lesions of comparable activity. Therefore, we analyzed the role of T-cell activation within the CNS in the initiation of NMO lesions in an experimental model of co-transfer of different encephalitogenic T-cells and human AQP4 antibody containing NMO immunoglobulin (NMO IgG). We further studied the expression of the T-cell activation marker Ox40 in NMO and multiple sclerosis lesions in different stages of activity.

Results: All encephalitogenic T-cell lines used in our experiments induced brain inflammation with a comparable extent of blood brain barrier damage, allowing human NMO IgG to penetrate into the brain and spinal cord tissue. However, astrocyte destructive NMO lesions were only seen with T-cells, which showed signs of activation in the lesions. T-cell activation was reflected by the expression of the activation marker Ox40 and pronounced production of γ-IFN, which was able to increase the production of complement proteins and of the Fc gamma III receptor (Fcgr3) and decreased production of complement inhibitory protein Factor H in microglia.

Conclusions: Our data indicate that local activation of T-cells provide an inflammatory environment in the CNS, which allows AQP4 auto-antibodies to induce astrocyte destructive NMO-like lesions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 4 / metabolism
  • Astrocytes / immunology
  • Astrocytes / pathology
  • Brain / immunology*
  • Brain / pathology
  • Cell Line
  • Cells, Cultured
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Immunoglobulin G / metabolism
  • Interferon-gamma / metabolism
  • Macrophages / immunology
  • Macrophages / pathology
  • Microglia / pathology
  • Microglia / physiology
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • Neuromyelitis Optica / immunology*
  • Neuromyelitis Optica / pathology
  • Rats, Inbred Lew
  • Receptors, IgG / metabolism
  • Spinal Cord / immunology*
  • Spinal Cord / pathology
  • T-Lymphocytes / pathology
  • T-Lymphocytes / physiology*

Substances

  • Aqp4 protein, rat
  • Aquaporin 4
  • Fcgr2a protein, rat
  • Immunoglobulin G
  • Receptors, IgG
  • Interferon-gamma