Fas-mediated apoptosis in clinical remissions of relapsing experimental autoimmune encephalomyelitis.
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.
Suvannavejh
G C
GC
Department of Microbiology-Immunology, Interdepartmental Immunobiology Center, Northwestern University Medical School and the Northwestern University Institute for Neuroscience, Chicago, Illinois 60611, USA.
Dal Canto
M C
MC
Matis
L A
LA
Miller
S D
SD
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002908:Chronic Disease; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology*; D053222:Fas Ligand Protein; D005260:Female; D020287:In Situ Nick-End Labeling; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012075:Remission, Spontaneous; D013116:Spinal Cord / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D012333:RNA, Messenger; D019014:fas Receptor; C435023:myelin proteolipid protein (139-151)