Critical points of tumor necrosis factor action in central nervous system autoimmune inflammation defined by gene targeting.
Tumor necrosis factor (TNF)-dependent sites of action in the generation of autoimmune inflammation have been defined by targeted disruption of TNF in the C57BL/6 mouse strain. C57BL/6 mice are susceptible to an inflammatory, demyelinating form of experimental autoimmune encephalomyelitis (EAE) induced by the 35-55 peptide of myelin oligodendrocyte glycoprotein. Direct targeting of a strain in which EAE was inducible was necessary, as the location of the TNF gene renders segregation of the mutated allele from the original major histocompatibility complex by backcrossing virtually impossible. In this way a single gene effect was studied. We show here that TNF is obligatory for normal initiation of the neurological deficit, as demonstrated by a significant (6 d) delay in disease in its absence relative to wild-type (WT) mice. During this delay, comparable numbers of leukocytes were isolated from the perfused central nervous system (CNS) of WT and TNF-/- mice. However, in the TNF-/- mice, immunohistological analysis of CNS tissue indicated that leukocytes failed to form the typical mature perivascular cuffs observed in WT mice at this same time point. Severe EAE, including paralysis and widespread CNS perivascular inflammation, eventually developed without TNF. TNF-/- and WT mice recovered from the acute illness at the same time, such that the overall disease course in TNF-/- mice was only 60% of the course in control mice. Primary demyelination occurred in both WT and TNF-/- mice, although it was of variable magnitude. These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS. Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE.
Körner
H
H
Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Sydney, New South Wales, 2050 Australia.
Riminton
D S
DS
Strickland
D H
DH
Lemckert
F A
FA
Pollard
J D
JD
Sedgwick
J D
JD
D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002490:Central Nervous System / Q000098:blood supply / Q000276:immunology* / Q000473:pathology*; D003711:Demyelinating Diseases / Q000235:genetics / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D017353:Gene Deletion; D007111:Immunity, Cellular / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000502:physiology*
D007074:Immunoglobulin G; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D014409:Tumor Necrosis Factor-alpha