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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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CNS expression of EAE-associated inflammatory proteins changes in the absence of an IFN-γ signal MOG35-55-specific T cell lines were generated in either C57BL/6 or IFN-γ–deficient mice and polarized to a Th1 phenotype. T cells were injected IV into either C57BL/6 or IFN-γR–deficient mice at 1 × 107 cells/mouse. Between 24 and 48 h after disease onset, mRNA was extracted from spinal cord and cerebellum and examined for inflammatory expression patterns using real time PCR as described in Materials and methods. Moderate Th1 tissue was extracted from animals that exhibited classical clinical scores of 1–2 in the 24–48 h after onset. Severe Th1 tissue was extracted from mice that exhibited classical clinical scores of 2.5–3.5 during the same period. The cells used to induce the severe EAE were injected in parallel into IFN-γR–deficient mice (IFN-γR ). The tissue in the IFN-γ– group was extracted from WT mice that received IFN-γ–deficient pathogenic T cells. The data are presented as mean ± SEM of 4–5 mice/group from two independent experiments.
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fig5: CNS expression of EAE-associated inflammatory proteins changes in the absence of an IFN-γ signal MOG35-55-specific T cell lines were generated in either C57BL/6 or IFN-γ–deficient mice and polarized to a Th1 phenotype. T cells were injected IV into either C57BL/6 or IFN-γR–deficient mice at 1 × 107 cells/mouse. Between 24 and 48 h after disease onset, mRNA was extracted from spinal cord and cerebellum and examined for inflammatory expression patterns using real time PCR as described in Materials and methods. Moderate Th1 tissue was extracted from animals that exhibited classical clinical scores of 1–2 in the 24–48 h after onset. Severe Th1 tissue was extracted from mice that exhibited classical clinical scores of 2.5–3.5 during the same period. The cells used to induce the severe EAE were injected in parallel into IFN-γR–deficient mice (IFN-γR ). The tissue in the IFN-γ– group was extracted from WT mice that received IFN-γ–deficient pathogenic T cells. The data are presented as mean ± SEM of 4–5 mice/group from two independent experiments.

Mentions: We then used real-time PCR to examine the cerebellum and spinal cord of mice with either classical or atypical EAE for tissue expression of a variety of molecules previously implicated in CNS autoimmunity (Fig. 5). Global differences in cerebellar expression of the IFN-γ–inducible chemokines CXCL9 and CXCL10 were observed when tissue from typical and atypical EAE were compared (Fig. 5). In addition there were significant reductions in the production of IFN-γ in mice that received IFN-γ–deficient cells and reduction in the production of TNF-α in IFN-γR–deficient mice (Fig. 5).


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)

CNS expression of EAE-associated inflammatory proteins changes in the absence of an IFN-γ signal MOG35-55-specific T cell lines were generated in either C57BL/6 or IFN-γ–deficient mice and polarized to a Th1 phenotype. T cells were injected IV into either C57BL/6 or IFN-γR–deficient mice at 1 × 107 cells/mouse. Between 24 and 48 h after disease onset, mRNA was extracted from spinal cord and cerebellum and examined for inflammatory expression patterns using real time PCR as described in Materials and methods. Moderate Th1 tissue was extracted from animals that exhibited classical clinical scores of 1–2 in the 24–48 h after onset. Severe Th1 tissue was extracted from mice that exhibited classical clinical scores of 2.5–3.5 during the same period. The cells used to induce the severe EAE were injected in parallel into IFN-γR–deficient mice (IFN-γR ). The tissue in the IFN-γ– group was extracted from WT mice that received IFN-γ–deficient pathogenic T cells. The data are presented as mean ± SEM of 4–5 mice/group from two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: CNS expression of EAE-associated inflammatory proteins changes in the absence of an IFN-γ signal MOG35-55-specific T cell lines were generated in either C57BL/6 or IFN-γ–deficient mice and polarized to a Th1 phenotype. T cells were injected IV into either C57BL/6 or IFN-γR–deficient mice at 1 × 107 cells/mouse. Between 24 and 48 h after disease onset, mRNA was extracted from spinal cord and cerebellum and examined for inflammatory expression patterns using real time PCR as described in Materials and methods. Moderate Th1 tissue was extracted from animals that exhibited classical clinical scores of 1–2 in the 24–48 h after onset. Severe Th1 tissue was extracted from mice that exhibited classical clinical scores of 2.5–3.5 during the same period. The cells used to induce the severe EAE were injected in parallel into IFN-γR–deficient mice (IFN-γR ). The tissue in the IFN-γ– group was extracted from WT mice that received IFN-γ–deficient pathogenic T cells. The data are presented as mean ± SEM of 4–5 mice/group from two independent experiments.
Mentions: We then used real-time PCR to examine the cerebellum and spinal cord of mice with either classical or atypical EAE for tissue expression of a variety of molecules previously implicated in CNS autoimmunity (Fig. 5). Global differences in cerebellar expression of the IFN-γ–inducible chemokines CXCL9 and CXCL10 were observed when tissue from typical and atypical EAE were compared (Fig. 5). In addition there were significant reductions in the production of IFN-γ in mice that received IFN-γ–deficient cells and reduction in the production of TNF-α in IFN-γR–deficient mice (Fig. 5).

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