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Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis.

Lees JR, Golumbek PT, Sim J, Dorsey D, Russell JH - J. Exp. Med. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

ABSTRACT
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.

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Adoptive transfer of Th1-polarized T cell lines generated in IFN-γ–deficient mice results in atypical CNS inflammation. MOG35-55-specific T cell lines were generated in either C57BL/6 (WT Th1) or IFN-γ–deficient (IFN-γ−/− Th1) mice. T cells were i.v. injected into WT mice at 5 × 106 cells/mouse. (A) 17 d after injection, spinal cord (top) and cerebellum (bottom) were collected and stained with hematoxylin and eosin (H&E) to reveal inflammation. (B) Brain stem sections from mice that received IFN-γ−/− Th1 were stained with H&E to reveal inflammation. (C) A higher magnification of brain stem sections stained with H&E was used to examine infiltrating cell composition. Arrows mark polymorphonuclear cells (PMN), monocytes (Mo), and lymphocytes (L). All slides shown are representative of sections taken from 12 mice per group over six separate experiments. Bars: (A and B) 200 μm; (C) 50 μm.
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fig1: Adoptive transfer of Th1-polarized T cell lines generated in IFN-γ–deficient mice results in atypical CNS inflammation. MOG35-55-specific T cell lines were generated in either C57BL/6 (WT Th1) or IFN-γ–deficient (IFN-γ−/− Th1) mice. T cells were i.v. injected into WT mice at 5 × 106 cells/mouse. (A) 17 d after injection, spinal cord (top) and cerebellum (bottom) were collected and stained with hematoxylin and eosin (H&E) to reveal inflammation. (B) Brain stem sections from mice that received IFN-γ−/− Th1 were stained with H&E to reveal inflammation. (C) A higher magnification of brain stem sections stained with H&E was used to examine infiltrating cell composition. Arrows mark polymorphonuclear cells (PMN), monocytes (Mo), and lymphocytes (L). All slides shown are representative of sections taken from 12 mice per group over six separate experiments. Bars: (A and B) 200 μm; (C) 50 μm.

Mentions: As previously reported, we found that transfer of IFN-γ–deficient Th1-polarized CNS antigen-specific activated CD4+ T cells resulted in an atypical clinical course of EAE (7, 12). The most common clinical symptoms noted were vertigo/dysequilibrium, as measured by a mouse's tendency to lean, turn, and/or roll to one side, and ataxia (Table I). Some mice also demonstrated symptoms of limb dysfunction associated with dystonia of the tail and limbs rather than the flaccid paralysis associated with classical EAE (Table I). Mice that received WT Th1 (IL12 treated) displayed classical EAE symptoms of ascending paralysis (Table I). The ascending paralysis was associated with monocytic inflammation of white matter tracts in the spinal cord, with negligible parenchymal infiltration of the cerebellum (Fig. 1 A).


Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis.

Lees JR, Golumbek PT, Sim J, Dorsey D, Russell JH - J. Exp. Med. (2008)

Adoptive transfer of Th1-polarized T cell lines generated in IFN-γ–deficient mice results in atypical CNS inflammation. MOG35-55-specific T cell lines were generated in either C57BL/6 (WT Th1) or IFN-γ–deficient (IFN-γ−/− Th1) mice. T cells were i.v. injected into WT mice at 5 × 106 cells/mouse. (A) 17 d after injection, spinal cord (top) and cerebellum (bottom) were collected and stained with hematoxylin and eosin (H&E) to reveal inflammation. (B) Brain stem sections from mice that received IFN-γ−/− Th1 were stained with H&E to reveal inflammation. (C) A higher magnification of brain stem sections stained with H&E was used to examine infiltrating cell composition. Arrows mark polymorphonuclear cells (PMN), monocytes (Mo), and lymphocytes (L). All slides shown are representative of sections taken from 12 mice per group over six separate experiments. Bars: (A and B) 200 μm; (C) 50 μm.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2571937&req=5

fig1: Adoptive transfer of Th1-polarized T cell lines generated in IFN-γ–deficient mice results in atypical CNS inflammation. MOG35-55-specific T cell lines were generated in either C57BL/6 (WT Th1) or IFN-γ–deficient (IFN-γ−/− Th1) mice. T cells were i.v. injected into WT mice at 5 × 106 cells/mouse. (A) 17 d after injection, spinal cord (top) and cerebellum (bottom) were collected and stained with hematoxylin and eosin (H&E) to reveal inflammation. (B) Brain stem sections from mice that received IFN-γ−/− Th1 were stained with H&E to reveal inflammation. (C) A higher magnification of brain stem sections stained with H&E was used to examine infiltrating cell composition. Arrows mark polymorphonuclear cells (PMN), monocytes (Mo), and lymphocytes (L). All slides shown are representative of sections taken from 12 mice per group over six separate experiments. Bars: (A and B) 200 μm; (C) 50 μm.
Mentions: As previously reported, we found that transfer of IFN-γ–deficient Th1-polarized CNS antigen-specific activated CD4+ T cells resulted in an atypical clinical course of EAE (7, 12). The most common clinical symptoms noted were vertigo/dysequilibrium, as measured by a mouse's tendency to lean, turn, and/or roll to one side, and ataxia (Table I). Some mice also demonstrated symptoms of limb dysfunction associated with dystonia of the tail and limbs rather than the flaccid paralysis associated with classical EAE (Table I). Mice that received WT Th1 (IL12 treated) displayed classical EAE symptoms of ascending paralysis (Table I). The ascending paralysis was associated with monocytic inflammation of white matter tracts in the spinal cord, with negligible parenchymal infiltration of the cerebellum (Fig. 1 A).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus