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Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals


Derfuss, T; Parikh, K; Velhin, S; Braun, M; Mathey, E; Krumbholz, M; Kümpfel, T; Moldenhauer, A; Rader, C; Sonderegger, P; Pöllmann, W; Tiefenthaller, C; Bauer, J; Lassmann, H; Wekerle, H; Karagogeos, D; Hohlfeld, R; Linington, C; Meinl, E (2009). Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 106(20):8302-8307.

Abstract

Gray matter pathology is increasingly recognized as an important feature of multiple sclerosis (MS), but the nature of the immune response that targets the gray matter is poorly understood. Starting with a proteomics approach, we identified contactin-2/transiently expressed axonal glycoprotein 1 (TAG-1) as a candidate autoantigen recognized by both autoantibodies and T helper (Th) 1/Th17 T cells in MS patients. Contactin-2 and its rat homologue, TAG-1, are expressed by various neuronal populations and sequestered in the juxtaparanodal domain of myelinated axons both at the axonal and myelin sides. The pathogenic significance of these autoimmune responses was then explored in experimental autoimmune encephalitis models in the rat. Adoptive transfer of TAG-1-specific T cells induced encephalitis characterized by a preferential inflammation of gray matter of the spinal cord and cortex. Cotransfer of TAG-1-specific T cells with a myelin oligodendrocyte glycoprotein-specific mAb generated focal perivascular demyelinating lesions in the cortex and extensive demyelination in spinal cord gray and white matter. This study identifies contactin-2 as an autoantigen targeted by T cells and autoantibodies in MS. Our findings suggest that a contactin-2-specific T-cell response contributes to the development of gray matter pathology.

Abstract

Gray matter pathology is increasingly recognized as an important feature of multiple sclerosis (MS), but the nature of the immune response that targets the gray matter is poorly understood. Starting with a proteomics approach, we identified contactin-2/transiently expressed axonal glycoprotein 1 (TAG-1) as a candidate autoantigen recognized by both autoantibodies and T helper (Th) 1/Th17 T cells in MS patients. Contactin-2 and its rat homologue, TAG-1, are expressed by various neuronal populations and sequestered in the juxtaparanodal domain of myelinated axons both at the axonal and myelin sides. The pathogenic significance of these autoimmune responses was then explored in experimental autoimmune encephalitis models in the rat. Adoptive transfer of TAG-1-specific T cells induced encephalitis characterized by a preferential inflammation of gray matter of the spinal cord and cortex. Cotransfer of TAG-1-specific T cells with a myelin oligodendrocyte glycoprotein-specific mAb generated focal perivascular demyelinating lesions in the cortex and extensive demyelination in spinal cord gray and white matter. This study identifies contactin-2 as an autoantigen targeted by T cells and autoantibodies in MS. Our findings suggest that a contactin-2-specific T-cell response contributes to the development of gray matter pathology.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:19 May 2009
Deposited On:29 Jul 2009 08:47
Last Modified:05 Apr 2016 13:18
Publisher:National Academy of Sciences
ISSN:0027-8424
Publisher DOI:https://doi.org/10.1073/pnas.0901496106
Official URL:http://www.pnas.org/content/106/20/8302.full.pdf+html
PubMed ID:19416878

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