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

• Published in: The Journal of clinical investigation Vol. 105; no. 2; pp. 223 - 231
• Main Authors: Suvannavejh, G C, Dal Canto, M C, Matis, L A, Miller, S D
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-01-2000
• Subjects: Animals; Apoptosis - immunology; Chronic Disease; Disease Progression; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - immunology; Fas Ligand Protein; fas Receptor - genetics; fas Receptor - immunology; Female; In Situ Nick-End Labeling; Membrane Glycoproteins - genetics; Mice; Mice, Inbred Strains; Myelin Proteolipid Protein; Peptide Fragments; Polymerase Chain Reaction; Remission, Spontaneous; RNA, Messenger - metabolism; Spinal Cord - metabolism
• ISSN: 0021-9738
• DOI: 10.1172/jci8561

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.