Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis.
The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-gamma. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN-gamma deficient). We demonstrate, using an adoptive transfer system, that the ability of the central nervous system (CNS) to sense pathogenic T cell-produced IFN-gamma during EAE initiation determines the sites of CNS pathogenesis. Transfer of WT Th1 cells into IFN-gamma receptor-deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-gamma-deficient T cells to WT hosts. Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-gamma-deficient systems. Cotransfer of CNS antigen-specific WT Th1 cells with IFN-gamma-deficient T cells is sufficient to restore spinal cord invasion and block cerebellar and brain stem invasion. These data demonstrate that interaction between IFN-gamma and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Jason R
JR
Lees
Paul T
PT
Golumbek
Julia
J
Sim
Denise
D
Dorsey
John H
JH
Russell
D019264:Adoptive Transfer; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology*; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D020381:Interleukin-17; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor