Nitric-oxide-dependent and independent mechanisms of protection from CNS inflammation during Th1-mediated autoimmunity: evidence from EAE in iNOS KO mice.
Experimental autoimmune encephalomyelitis (EAE) disease was accelerated iNOS-deficient (KO) mice: coinciding with greatly increased numbers of Ag-specific Th1 cells in the periphery that appeared to rapidly shift from the spleen to the CNS during onset of disease symptoms. iNOS KO mice had significantly increased Th1 cells in the CNS versus wild-type mice. Apoptosis of CNS-infiltrating CD4(+) T cells was impaired in iNOS KO mice at peak of disease; consequently, these mice had more CNS-infiltrating CD4(+) T cells. Subsequently, iNOS KO mice up-regulated apoptosis of CNS-CD4(+) T cells. During chronic EAE, CNS macrophages were greatly decreased, suggesting elimination of CNS-infiltrating CD4(+) T cells and activated macrophages by iNOS-independent mechanisms. INOS is not only required for apoptosis of CNS-CD4(+) T cells but also prevents overexpansion of autoreactive Th1 cells in the periphery and the CNS.
Dalton
Dyana K
DK
Trudeau Institute Inc., 154 Algonquin Ave, Saranac Lake, NY 12983, USA. ddalton@trudeauinstitute.org
Wittmer
Susan
S
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D002908:Chronic Disease; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D012720:Severity of Illness Index; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology
D000276:Adjuvants, Immunologic; D018984:Epitopes, T-Lymphocyte; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse