Transglutaminase-6 is an autoantigen in progressive multiple sclerosis and is upregulated in reactive astrocytes

• Published in: Multiple sclerosis 2017-11, Vol.23 (13), p.1707-1715
• Main Authors: Cristofanilli, Massimiliano, Gratch, Daniel, Pagano, Benjamin, McDermott, Kelsey, Huang, Jessie, Jian, Jeffrey, Bates, Deneb, Sadiq, Saud A
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Astrocytes; Astrocytes - metabolism; Autoantibodies - cerebrospinal fluid; Autoantigens - immunology; Autopsy; Biomarkers - cerebrospinal fluid; Brain - metabolism; Cells, Cultured; Central nervous system; Cerebellar ataxia; Cerebellum; Cerebrospinal fluid; Encephalomyelitis, Autoimmune, Experimental - metabolism; Experimental allergic encephalomyelitis; Female; Glial fibrillary acidic protein; Gluten; Humans; Immunoglobulin G; Male; Mental disorders; Mice; Mice, Inbred C57BL; Middle Aged; Multiple sclerosis; Multiple Sclerosis, Chronic Progressive - cerebrospinal fluid; Multiple Sclerosis, Chronic Progressive - immunology; Multiple Sclerosis, Chronic Progressive - metabolism; Multiple Sclerosis, Relapsing-Remitting - cerebrospinal fluid; Multiple Sclerosis, Relapsing-Remitting - immunology; Multiple Sclerosis, Relapsing-Remitting - metabolism; Paralysis; Plaques; Rodents; Schizophrenia; Spinal cord; Substantia alba; Transglutaminases - immunology; Transglutaminases - metabolism; Up-Regulation
• ISSN: 1352-4585; 1477-0970
• DOI: 10.1177/1352458516684022

Background: Transglutaminase-6 (TGM6), a member of the transglutaminase enzyme family, is found predominantly in central nervous system (CNS) neurons under physiological conditions. It has been proposed as an autoimmune target in cerebral palsy, gluten-sensitive cerebellar ataxia, and schizophrenia. Objective: To investigate TGM6 involvement in multiple sclerosis (MS). Methods: Antibody levels against TGM6 (TGM6-IgG) were measured in the cerebrospinal fluid (CSF) of 62 primary progressive multiple sclerosis (PPMS), 85 secondary progressive multiple sclerosis (SPMS), and 50 relapsing-remitting multiple sclerosis (RRMS) patients and 51 controls. TGM6 protein expression was analyzed in MS brain autopsy, murine experimental autoimmune encephalomyelitis (EAE), and cultured astrocytes. Results: CSF levels of TGM6-IgG were significantly higher in PPMS and SPMS compared to RRMS and controls. Notably, patients with clinically active disease had the highest TGM6-IgG levels. Additionally, brain pathology revealed strong TGM6 expression by reactive astrocytes within MS plaques. In EAE, TGM6 expression in the spinal cord correlated with disease course and localized in reactive astrocytes infiltrating white matter lesions. Finally, knocking down TGM6 expression in cultured reactive astrocytes reduced their glial fibrillary acidic protein (GFAP) expression. Conclusion: TGM6-IgG may be a candidate CSF biomarker to predict and monitor disease activity in progressive MS patients. Furthermore, TGM6 expression by reactive astrocytes within both human and mouse lesions suggests its involvement in the mechanisms of glial scar formation.