Kit (W-sh) mice develop earlier and more severe experimental autoimmune encephalomyelitis due to absence of immune suppression

J Immunol. 2011 Jul 1;187(1):274-82. doi: 10.4049/jimmunol.1003603. Epub 2011 Jun 6.

Abstract

Mast cells (MCs) have been thought to play a pathogenic role in the development of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, an immunoregulatory function of these cells has recently been suggested. We investigated the role of MCs in EAE using the W(-sh) mouse strain, which is MC deficient. W(-sh) mice developed earlier and more severe clinical and pathological disease with extensive demyelination and inflammation in the CNS. The inflammatory cells were mainly composed of CD4(+) T cells, monocyte/macrophages, neutrophils, and dendritic cells. Compared with wild-type mice, MC-deficient mice exhibited an increased level of MCP-1/CCR2 and CD44 expression on CD4(+) T cells in addition to decreased production of regulatory T cells, IL-4, IL-5, IL-27, and IL-10. We also found that levels of IL-17, IFN-γ, and GM-CSF were significantly increased in peripheral lymphocytes from immunized W(-sh) mice compared with those in peripheral lymphocytes from wild-type mice. Reconstitution of W(-sh) mice downregulated susceptibility to EAE, which correlated with MC recruitment and regulatory T cell activation in the CNS. These findings indicate that responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS and that, in the absence of MCs, increased MCP-1, CCR2, IL-17, IFN-γ, CD44, and other inflammatory molecules may be responsible for increased severity of EAE.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Encephalomyelitis, Autoimmune, Experimental / genetics*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Genetic Predisposition to Disease
  • Immune Tolerance / genetics*
  • Immune Tolerance / immunology*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Mast Cells / immunology*
  • Mast Cells / pathology*
  • Mice
  • Myelin Proteins
  • Myelin-Associated Glycoprotein / administration & dosage
  • Myelin-Associated Glycoprotein / toxicity
  • Myelin-Oligodendrocyte Glycoprotein
  • Proto-Oncogene Proteins c-kit / deficiency*
  • Proto-Oncogene Proteins c-kit / genetics
  • Severity of Illness Index*
  • Spinal Cord / immunology
  • Spinal Cord / pathology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology

Substances

  • Mog protein, mouse
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Myelin-Oligodendrocyte Glycoprotein
  • Proto-Oncogene Proteins c-kit