PT  - JOURNAL ARTICLE
AU  - Sestito, Claudia
AU  - Leurs, Cyra E.
AU  - Steenwijk, Martijn D.
AU  - Brevé, John J.P.
AU  - Twisk, Jos W.R.
AU  - Wilhelmus, Micha M.M.
AU  - Drukarch, Benjamin
AU  - Teunissen, Charlotte E.
AU  - van Dam, Anne-Marie
AU  - Killestein, Joep
TI  - Tissue Transglutaminase Expression Associates With Progression of Multiple Sclerosis
AID  - 10.1212/NXI.0000000000000998
DP  - 2021 Jul 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e998
VI  - 8
IP  - 4
4099  - http://nn.neurology.org/content/8/4/e998.short
4100  - http://nn.neurology.org/content/8/4/e998.full
SO  - Neurol Neuroimmunol Neuroinflamm2021 Jul 01; 8
AB  - Objective The clinical course of multiple sclerosis (MS) is variable and largely unpredictable pointing to an urgent need for markers to monitor disease activity and progression. Recent evidence revealed that tissue transglutaminase (TG2) is altered in patient-derived monocytes. We hypothesize that blood cell–derived TG2 messenger RNA (mRNA) can potentially be used as biomarker in patients with MS.Methods In peripheral blood mononuclear cells (PBMCs) from 151 healthy controls and 161 patients with MS, TG2 mRNA was measured and correlated with clinical and MRI parameters of disease activity (annualized relapse rate, gadolinium-enhanced lesions, and T2 lesion volume) and disease progression (Expanded Disability Status Scale [EDSS], normalized brain volume, and hypointense T1 lesion volume).Results PBMC-derived TG2 mRNA levels were significantly associated with disease progression, i.e., worsening of the EDSS over 2 years of follow-up, normalized brain volume, and normalized gray and white matter volume in the total MS patient group at baseline. Of these, in patients with relapsing-remitting MS, TG2 expression was significantly associated with worsening of the EDSS scores over 2 years of follow-up. In the patients with primary progressive (PP) MS, TG2 mRNA levels were significantly associated with EDSS, normalized brain volume, and normalized gray and white matter volume at baseline. In addition, TG2 mRNA associated with T1 hypointense lesion volume in the patients with PP MS at baseline.Conclusion PBMC-derived TG2 mRNA levels hold promise as biomarker for disease progression in patients with MS.Classification of Evidence This study provides Class II evidence that in patients with MS, PBMC-derived TG2 mRNA levels are associated with disease progression.3D=3 dimensional; ARR=annualized relapse rate; cDNA=complementary DNA; DMD=disease-modifying drug; EAE=experimental autoimmune encephalomyelitis; EDSS=Expanded Disability Status Scale; HC=healthy control; HPRT1=hypoxanthine phosphoribosyltransferase 1; IQR=interquartile range; mRNA=messenger RNA; MS=multiple sclerosis; NBV=normalized total brain volume; NfL=neurofilament light chain; NGMV=normalized total gray matter volume; NWMV=normalized white matter volume; PBMC=peripheral blood mononuclear cell; PD=proton density; POLR2F=polymerase (RNA) II polypeptide F; PP=primary progressive; qPCR=quantitative real-time PCR; RR=relapsing-remitting; SP=secondary progressive; T1LV=lesion volumes T1 hypointense lesion; T2LV=lesion volumes for T2 lesions; TE=echo time; TG2=tissue transglutaminase; TI=inversion time; TR=repetition time