The Ohio State University
Neurology

Author Of 1 Presentation

Genetics and Epigenetics Late Breaking Abstracts

LB1236 - The role of ten eleven translocase 2 (TET2) in the regulation of autoimmune demyelinating disease (ID 2117)

Speakers
Authors
Presentation Number
LB1236
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Ten-Eleven Translocase 2 (TET2) is a Fe(III)-, α-ketoglutarate-dependent enzyme that catalyzes the oxidation of methylated cytosine to 5’-hydroxymethyl cytosine (5hmC). 5hmC is a stable epigenetic mark that can either activate or repress gene expression in a cell- and loci-dependent manner. Recently Tet-2 was identified as a genetic susceptibility locus in MS. TET2 loss-of-function mutations are abundant in a variety of cancers characterized by aberrant myeloid proliferation, differentiation, and activation. Since myeloid cells play a critical role in the pathogenesis of Multiple sclerosis (MS) and the animal model experimental autoimmune encephalitis (EAE), we hypothesized that Tet-2 reduction or inactivation in myeloid cells promotes susceptibility to autoimmune demyelinating disease.

Objectives

To measure the expression of Tet2 and 5hmC in CNS-infiltrating myeloid cells during the development of adoptively transferred EAE, and to assess the impact of Tet2 deficiency on the clinical course.

Methods

EAE was induced via adoptive transfer of Th17-polarized, myelin oligodendrocyte glycoprotein (MOG)-specific CD4+ T cells in WT and Tet2+/- mice. CNS mononuclear cells and splenocytes were analyzed via flow cytometry and transcriptomics.

Results

Tet2, 5hmC content, and markers of Tet2 activity, were reduced in CNS-infiltrating monocytes, macrophages and monocyte derived dendritic cells at the peak of EAE compared with their splenic counterparts. Tet2+/- mice experienced an exacerbated clinical course of Th17-mediated EAE compared to Tet2+/+ mice. The increase in disease severity was associated with hyperactivation of CNS myeloid cells. Ongoing studies in our laboratory are examining the effects of a myeloid-specific TET2 deletion on neuroinflammation and CNS damage during EAE using a Cre/lox genetic system.

Conclusions

Our data suggest that downregulation of TET2 expression and activity during EAE enhances neuroinflammation, CNS damage and neurological disability. This study elucidates a novel mechanism of myeloid cell regulation during CNS autoimmune disease. Disease modifying therapies that prevent Tet2 downregulation in myeloid cells may be beneficial in individuals with MS and related disorders who do not respond to lymphocyte targeting agents.

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Presenter Of 1 Presentation

Genetics and Epigenetics Late Breaking Abstracts

LB1236 - The role of ten eleven translocase 2 (TET2) in the regulation of autoimmune demyelinating disease (ID 2117)

Speakers
Authors
Presentation Number
LB1236
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Ten-Eleven Translocase 2 (TET2) is a Fe(III)-, α-ketoglutarate-dependent enzyme that catalyzes the oxidation of methylated cytosine to 5’-hydroxymethyl cytosine (5hmC). 5hmC is a stable epigenetic mark that can either activate or repress gene expression in a cell- and loci-dependent manner. Recently Tet-2 was identified as a genetic susceptibility locus in MS. TET2 loss-of-function mutations are abundant in a variety of cancers characterized by aberrant myeloid proliferation, differentiation, and activation. Since myeloid cells play a critical role in the pathogenesis of Multiple sclerosis (MS) and the animal model experimental autoimmune encephalitis (EAE), we hypothesized that Tet-2 reduction or inactivation in myeloid cells promotes susceptibility to autoimmune demyelinating disease.

Objectives

To measure the expression of Tet2 and 5hmC in CNS-infiltrating myeloid cells during the development of adoptively transferred EAE, and to assess the impact of Tet2 deficiency on the clinical course.

Methods

EAE was induced via adoptive transfer of Th17-polarized, myelin oligodendrocyte glycoprotein (MOG)-specific CD4+ T cells in WT and Tet2+/- mice. CNS mononuclear cells and splenocytes were analyzed via flow cytometry and transcriptomics.

Results

Tet2, 5hmC content, and markers of Tet2 activity, were reduced in CNS-infiltrating monocytes, macrophages and monocyte derived dendritic cells at the peak of EAE compared with their splenic counterparts. Tet2+/- mice experienced an exacerbated clinical course of Th17-mediated EAE compared to Tet2+/+ mice. The increase in disease severity was associated with hyperactivation of CNS myeloid cells. Ongoing studies in our laboratory are examining the effects of a myeloid-specific TET2 deletion on neuroinflammation and CNS damage during EAE using a Cre/lox genetic system.

Conclusions

Our data suggest that downregulation of TET2 expression and activity during EAE enhances neuroinflammation, CNS damage and neurological disability. This study elucidates a novel mechanism of myeloid cell regulation during CNS autoimmune disease. Disease modifying therapies that prevent Tet2 downregulation in myeloid cells may be beneficial in individuals with MS and related disorders who do not respond to lymphocyte targeting agents.

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