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.

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.

Keywords

Progressive multiple sclerosis transglutaminase-6 cerebrospinal fluid autoantigen EAE reactive astrocytes

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References

Lassmann

. Mechanisms of demyelination and tissue destruction in multiple sclerosis. Clin Neurol Neurosurg 2002; 104: 168–171.

Hemmer

Cepok

Nessler

et al . Pathogenesis of multiple sclerosis: An update on immunology. Curr Opin Neurol 2002; 15: 227–231.

Gironi

Bergami

Brambilla

et al . Immunological markers in multiple sclerosis. Neurol Sci 2000; 21: S871–S875.

Compston

Coles

. Multiple sclerosis. Lancet 2008; 372: 1502–1517.

Ridet

Malhotra

Privat

et al . Reactive astrocytes: Cellular and molecular cues to biological function. Trends Neurosci 1997; 20: 570–577.

Sofroniew

. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 2009; 32: 638–647.

Brambilla

Morton

Jopek

et al . Astrocytes play a key role in eae pathophysiology by orchestrating in the cns the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. GLIA 2014; 62: 452–467.

Voskuhl

Peterson

Song

et al . Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS. J Neurosci 2009; 29: 11511–11522.

Aeschlimann

Thomazy

Protein crosslinking in assembly and remodelling of extracellular matrices: the role of transglutaminases. Connect Tissue Res 2000; 41: 1–27.

10.

Iismaa

Mearns

Lorand

Graham

RM.

Transglutaminases and disease: lessons from genetically engineered mouse models and inherited disorders. Physiol Rev 2009; 89: 991–1023.

11.

Jeitner

Muma

Battaile

Cooper

AJ.

Transglutaminase activation in neurodegenerative diseases. Future Neurol 2009; 4: 449–467.

12.

Gadoth

Nefussy

Bleiberg

et al . Transglutaminase 6 antibodies in the serum of patients with amyotrophic lateral sclerosis. JAMA Neurol 2015; 72: 676–681.

13.

Stenberg

Hadjivassiliou

Aeschlimann

et al . Anti-transglutaminase 6 antibodies in children and young adults with cerebral palsy. Autoimmun Dis 2014; 2014: 237107.

14.

Hadjivassiliou

Aeschlimann

Strigun

et al . Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol 2008; 64: 332–343.

15.

Hadjivassiliou

Aeschlimann

Sanders

et al . Transglutaminase 6 antibodies in the diagnosis of gluten ataxia. Neurology 2013; 80: 1740–1745.

16.

Cascella

Santora

Gregory

et al . Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr Bull 2013; 39: 867–871.

17.

Park

Seo

et al . Transglutaminase 2 exacerbates experimental autoimmune encephalomyelitis through positive regulation of encephalitogenic T cell differentiation and inflammation. Clin Immunol 2012; 145: 122–132.

18.

Van Strien

Breve

Fratantoni

et al . Astrocyte-derived tissue transglutaminase interacts with fibronectin: A role in astrocyte adhesion and migration? PLoS ONE 2011; 6: e25037.

19.

Van Strien

Drukarch

Bol

et al . Appearance of tissue transglutaminase in astrocytes in multiple sclerosis lesions: A role in cell adhesion and migration? Brain Pathol 2011; 21: 44–54.

20.

McDonald

Compston

Edan

et al . Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.

21.

Stromnes

Goverman

. Active induction of experimental allergic encephalomyelitis. Nat Protoc 2006; 1: 1810–1819.

22.

Thomas

Beck

Adamczyk

et al . Transglutaminase 6: A protein associated with central nervous system development and motor function. Amino Acids 2013; 44: 161–177.

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