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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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Related in: MedlinePlus

Deficiency of either IFN-γ or IFN-γR results in inflammation of the cerebellum after adoptive transfer of CNS pathogenic T cells. MOG35-55-specific T cell lines were generated in either C57BL/6 (WT Th1) or IFN-γ–deficient (IFN-γ KO Th1) mice in the presence of IL-12. T cells were i.v. injected into either C57BL/6 (WT) or IFN-γR–deficient (IFN-γR KO) mice at 5 × 106 cells/mouse. 17 d after injection, spinal cord and cerebellum were collected and stained with H&E to reveal inflammation. Perivascular lesions and invasive parenchymal lesions are indicated with an arrow and the letters P and I, respectively. Representative slides from three independent experiments are shown. Bars, 200 μm.
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fig4: Deficiency of either IFN-γ or IFN-γR results in inflammation of the cerebellum after adoptive transfer of CNS pathogenic T cells. MOG35-55-specific T cell lines were generated in either C57BL/6 (WT Th1) or IFN-γ–deficient (IFN-γ KO Th1) mice in the presence of IL-12. T cells were i.v. injected into either C57BL/6 (WT) or IFN-γR–deficient (IFN-γR KO) mice at 5 × 106 cells/mouse. 17 d after injection, spinal cord and cerebellum were collected and stained with H&E to reveal inflammation. Perivascular lesions and invasive parenchymal lesions are indicated with an arrow and the letters P and I, respectively. Representative slides from three independent experiments are shown. Bars, 200 μm.

Mentions: After transfer of WT MOG-specific pathogenic T cells, IFN-γ receptor (IFN-γR)–deficient mice developed an atypical disease identical to that observed with transfer of IFN-γ–deficient effector T cells into WT hosts (Table III). In addition to the appearance of identical clinical symptoms, transfer of WT encephalitogenic T cells resulted in histopathology very similar to that seen after transfer of IFN-γ–deficient cells into WT hosts (Fig. 4). Thus, the IFN-γ–IFN-γR interactions involved in determining regions of inflammatory pathology within the CNS occur long after T cell lineage commitment. These data indicate that the determination of regional inflammatory sites most likely occurs during the invasion process itself and involves input from the site of tissue inflammation.


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)

Deficiency of either IFN-γ or IFN-γR results in inflammation of the cerebellum after adoptive transfer of CNS pathogenic T cells. MOG35-55-specific T cell lines were generated in either C57BL/6 (WT Th1) or IFN-γ–deficient (IFN-γ KO Th1) mice in the presence of IL-12. T cells were i.v. injected into either C57BL/6 (WT) or IFN-γR–deficient (IFN-γR KO) mice at 5 × 106 cells/mouse. 17 d after injection, spinal cord and cerebellum were collected and stained with H&E to reveal inflammation. Perivascular lesions and invasive parenchymal lesions are indicated with an arrow and the letters P and I, respectively. Representative slides from three independent experiments are shown. Bars, 200 μm.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571937&req=5

fig4: Deficiency of either IFN-γ or IFN-γR results in inflammation of the cerebellum after adoptive transfer of CNS pathogenic T cells. MOG35-55-specific T cell lines were generated in either C57BL/6 (WT Th1) or IFN-γ–deficient (IFN-γ KO Th1) mice in the presence of IL-12. T cells were i.v. injected into either C57BL/6 (WT) or IFN-γR–deficient (IFN-γR KO) mice at 5 × 106 cells/mouse. 17 d after injection, spinal cord and cerebellum were collected and stained with H&E to reveal inflammation. Perivascular lesions and invasive parenchymal lesions are indicated with an arrow and the letters P and I, respectively. Representative slides from three independent experiments are shown. Bars, 200 μm.
Mentions: After transfer of WT MOG-specific pathogenic T cells, IFN-γ receptor (IFN-γR)–deficient mice developed an atypical disease identical to that observed with transfer of IFN-γ–deficient effector T cells into WT hosts (Table III). In addition to the appearance of identical clinical symptoms, transfer of WT encephalitogenic T cells resulted in histopathology very similar to that seen after transfer of IFN-γ–deficient cells into WT hosts (Fig. 4). Thus, the IFN-γ–IFN-γR interactions involved in determining regions of inflammatory pathology within the CNS occur long after T cell lineage commitment. These data indicate that the determination of regional inflammatory sites most likely occurs during the invasion process itself and involves input from the site of tissue inflammation.

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