Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals.
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.
Derfuss
Tobias
T
Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany.
Parikh
Khyati
K
Velhin
Sviataslau
S
Braun
Magdalena
M
Mathey
Emily
E
Krumbholz
Markus
M
Kümpfel
Tania
T
Moldenhauer
Anja
A
Rader
Christoph
C
Sonderegger
Peter
P
Pöllmann
Walter
W
Tiefenthaller
Christian
C
Bauer
Jan
J
Lassmann
Hans
H
Wekerle
Hartmut
H
Karagogeos
Domna
D
Hohlfeld
Reinhard
R
Linington
Christopher
C
Meinl
Edgar
E
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens; D015551:Autoimmunity; D015816:Cell Adhesion Molecules, Neuronal / Q000276:immunology*; D058969:Contactin 2; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D006801:Humans; D009103:Multiple Sclerosis / Q000209:etiology / Q000276:immunology*; D036421:Nerve Fibers, Unmyelinated / Q000473:pathology*; D051381:Rats; D013601:T-Lymphocytes / Q000637:transplantation
D001324:Autoantigens; C548674:CNTN2 protein, human; D015816:Cell Adhesion Molecules, Neuronal; C548676:Cntn2 protein, rat; D058969:Contactin 2