Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis

J Clin Invest. 2000 Jan;105(2):223-31. doi: 10.1172/JCI8561.

Abstract

PLP139-51-induced experimental autoimmune encephalomyelitis (R-EAE) displays a relapsing-remitting paralytic course in female SJL mice. We investigated the role of apoptosis/activation-induced cell death (AICD) in the spontaneous recovery from acute disease. Clinical EAE was significantly enhanced in Fas (CD95/APO-1)-deficient SJL lpr/lpr mice, which displayed significantly increased mean peak clinical scores, reduced remission rates, and increased mortality when compared with their SJL +/lpr littermates. PLP139-151-specific proliferative responses were fairly equivalent in the 2 groups, but draining lymph node T cells from SJL lpr/lpr mice produced dramatically increased levels of IFN-gamma. Central nervous system (CNS) Fas and FasL mRNA levels in wild-type SJL (H-2(s)) mice peaked just before spontaneous disease remission and gradually declined as disease remitted. We applied the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay to detect apoptosis in situ in spinal cords of mice at various clinical stages of EAE. Most TUNEL(+) cells were found during active periods of inflammation: the acute, peak, and relapse time points. Significantly fewer apoptotic cells were observed at preclinical and remission time points. Collectively, these findings indicate that Fas-mediated apoptosis/AICD plays a major role in the spontaneous remission after the initial acute inflammatory episode and represents an important intrinsic mechanism in regulation of autoimmune responses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Chronic Disease
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Fas Ligand Protein
  • Female
  • In Situ Nick-End Labeling
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred Strains
  • Myelin Proteolipid Protein
  • Peptide Fragments
  • Polymerase Chain Reaction
  • RNA, Messenger / metabolism
  • Remission, Spontaneous
  • Spinal Cord / metabolism
  • fas Receptor / genetics
  • fas Receptor / immunology*

Substances

  • Fas Ligand Protein
  • Fasl protein, mouse
  • Membrane Glycoproteins
  • Myelin Proteolipid Protein
  • Peptide Fragments
  • RNA, Messenger
  • fas Receptor
  • myelin proteolipid protein (139-151)