IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis

J Immunol. 2003 May 1;170(9):4776-84. doi: 10.4049/jimmunol.170.9.4776.

Abstract

Since the basic mechanisms behind the beneficial effects of IFN-beta in multiple sclerosis (MS) patients are still obscure, here we have investigated the effects of IFN-beta gene disruption on the commonly used animal model for MS, experimental autoimmune encephalomyelitis (EAE). We show that IFN-beta knockout (KO) mice are more susceptible to EAE than their wild-type (wt) littermates; they develop more severe and chronic neurological symptoms with more extensive CNS inflammation and demyelination. However, there was no discrepancy observed between wt and KO mice regarding the capacity of T cells to proliferate or produce IFN-gamma in response to recall Ag. Consequently, we addressed the effect of IFN-beta on encephalitogenic T cell development and the disease initiation phase by passive transfer of autoreactive T cells from KO or wt littermates to both groups of mice. Interestingly, IFN-beta KO mice acquired a higher incidence and augmented EAE regardless of the source of T cells. This shows that the anti-inflammatory effect of endogenous IFN-beta is predominantly exerted on the effector phase of the disease. Histopathological investigations of CNS in the effector phase revealed an extensive microglia activation and TNF-alpha production in IFN-beta KO mice; this was virtually absent in wt littermates. This coincided with an increase in effector functions of T cells in IFN-beta KO mice, as measured by IFN-gamma and IL-4 production. We suggest that lack of endogenous IFN-beta in CNS leads to augmented microglia activation, resulting in a sustained inflammation, cytokine production, and tissue damage with consequent chronic neurological deficits.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / genetics*
  • Adoptive Transfer
  • Animals
  • Autoantibodies / biosynthesis
  • Autoantigens / immunology
  • Cells, Cultured
  • Chronic Disease
  • Encephalomyelitis, Autoimmune, Experimental / epidemiology
  • Encephalomyelitis, Autoimmune, Experimental / genetics*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Deletion*
  • Genetic Predisposition to Disease
  • Immunophenotyping
  • Incidence
  • Inflammation / genetics
  • Inflammation / immunology
  • Interferon-beta / biosynthesis
  • Interferon-beta / deficiency*
  • Interferon-beta / genetics*
  • Macrophage Activation / genetics
  • Macrophage Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin Basic Protein / immunology
  • Myelin Sheath / pathology
  • Peptide Fragments / immunology
  • Severity of Illness Index
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / transplantation
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th2 Cells / immunology
  • Th2 Cells / metabolism

Substances

  • Adjuvants, Immunologic
  • Autoantibodies
  • Autoantigens
  • Myelin Basic Protein
  • Peptide Fragments
  • myelin basic protein 89-101
  • Interferon-beta