Superantigen overcomes resistance of IL-6-deficient mice towards MOG-induced EAE by a TNFR1 controlled pathway.
Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide 35-55 (MOG) leads to a chronic form of disease characterized by demyelination, inflammation and gliosis in the central nervous system (CNS). Recently IL-6 and LT alpha were found to be required for induction of the disease. The main features associated with EAE resistance of IL-6(-/-) and LT alpha(-/-) mice were reduced T cell proliferation and endothelial activation. As shown here treatment of MOG-immunized IL-6(-/-) mice with staphylococcal enterotoxin B (SEB)reversed their resistance to MOG-induced EAE. SEB failed to restore susceptibility to EAE in LT alpha(-/-) mice. The effect of SEB to induce EAE in IL-6(-/-) mice depends on TNF receptor type 1 (TNFR1) signaling because IL-6/TNF/LT alpha(-/-) and IL-6/TNFR1(-/-) are refractory to SEB. TNFR1 is involved in SEB induced trafficking of T cells into the CNS as evidenced by the failure to up-regulate VCAM-1 on CNS endothelium and lack of accumulation of V beta 8(+) T cells in the CNS of IL-6/TNFR1(-/-) mice upon immunization with MOG and treatment with SEB. The course of SEB triggered EAE in MOG immunized IL-6(-/-) mice was characterized by reduced severity and duration of clinical manifestations, which were associated with a significant drop of CNS infiltrating neutrophils and MIP-2 expression after peak disease. Taken collectively the effect of SEB to overcome EAE resistance points to a transient IL-6 independent but TNFR1 dependent proinflamatory pathway in EAE pathogenesis and suggests a crucial function for IL-6 in disease perpetuation.
Eugster
H P
HP
Section of Clinical Immunology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland.
Frei
K
K
Winkler
F
F
Koedel
U
U
Pfister
W
W
Lassmann
H
H
Fontana
A
A
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D002455:Cell Division; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology*; D004768:Enterotoxins / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009504:Neutrophils / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000187:drug effects; D018089:Superantigens / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015703:Antigens, CD; D016207:Cytokines; D004768:Enterotoxins; D015850:Interleukin-6; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C031818:enterotoxin B, staphylococcal