title: Transglutaminase-6 is an autoantigen in progressive multiple sclerosis and is upregulated in reactive astrocytes.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Tisch MS Research Center of New York, New York, NY, USA.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cristofanilli
authors.affiliation: Tisch MS Research Center of New York, New York, NY, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gratch
authors.affiliation: Tisch MS Research Center of New York, New York, NY, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Pagano
authors.affiliation: Tisch MS Research Center of New York, New York, NY, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: McDermott
authors.affiliation: Tisch MS Research Center of New York, New York, NY, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Tisch MS Research Center of New York, New York, NY, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jian
authors.affiliation: International Multiple Sclerosis Management Practice, New York, NY, USA.
authors.forename: Deneb
authors.initials: D
authors.lastname: Bates
authors.affiliation: Tisch MS Research Center of New York, New York, NY, USA.
authors.forename: Saud A
authors.initials: SA
authors.lastname: Sadiq
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001323:Autoantibodies / Q000134:cerebrospinal fluid*; D001324:Autoantigens / Q000276:immunology*; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000134:cerebrospinal fluid / Q000276:immunology / Q000378:metabolism; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000134:cerebrospinal fluid / Q000276:immunology / Q000378:metabolism; D011503:Transglutaminases / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D007074:Immunoglobulin G; C532876:TGM6 protein, human; D011503:Transglutaminases
keywords: EAE; Progressive multiple sclerosis; autoantigen; cerebrospinal fluid; reactive astrocytes; transglutaminase-6