High levels of serum soluble TWEAK are associated with neuroinflammation during multiple sclerosis

Abstract

Background: Inflammation and demyelination are the main processes in multiple sclerosis. Nevertheless, to date, blood biomarkers of inflammation are lacking. TWEAK, a transmembrane protein that belongs to the TNF ligand family, has been previously identified as a potential candidate.

Methods: Twenty-eight patients (9 males, 19 females) were prospectively included after a first clinical episode suggestive of multiple sclerosis and clinically followed during 3 years. Fifty-seven healthy controls were also included. TWEAK serum levels and MRI exams including magnetization transfer imaging were performed at baseline, 6- and 12-month follow-up.

Results: TWEAK serum levels were significantly increased in the patient group (mean baseline = 1086 ± 493 pg/mL, mean M6 = 624 ± 302 pg/mL and mean M12 = 578 ± 245 pg/mL) compared to healthy controls (mean = 467 ± 177 pg/mL; respectively p < 0.0001, 0.01 and 0.06). Serum levels of soluble TWEAK were significantly increased during relapses, compared to time periods without any relapse (respectively 935 ± 489 pg/mL and 611 ± 292 pg/mL, p = 0.0005). Moreover, patients presenting at least one gadolinium-enhanced CNS lesion at baseline (n = 7) displayed significantly increased serum TWEAK levels in comparison with patients without any gadolinium-enhanced lesion at baseline (n = 21) (respectively 1421 ± 657 pg/mL vs 975 ± 382 pg/mL; p = 0.02). Finally, no correlation was evidenced between TWEAK serum levels and the extent of brain tissue damage assessed by magnetization transfer ratio.

Conclusions: The present study showed that TWEAK serum levels are increased in MS patients, in relation to the disease activity. This simple and reproducible serum test could be used as a marker of ongoing inflammation, contributing in the follow-up and the care of MS patients. Thus, TWEAK is a promising serum marker of the best window to perform brain MRI, optimizing the disease control in patients.

Keywords: Biomarker; Cytokine; Multiple sclerosis; Neuroinflammation; TWEAK.

Fig. 1

TWEAK serum levels at baseline. a TWEAK serum level values for each patient and each control at baseline. TWEAK serum levels were increased in the patient group (mean = 1086 ± 493 pg/mL) compared to healthy controls (mean = 467 ± 177 pg/mL; p < 0.0001); b ROC analysis showing a sensitivity of 68% and a specificity of 96% for TWEAK serum levels to distinguish patients from controls for a value of 803 pg/mL; Elevated TWEAK serum levels were not associated with c serum monocyte levels (p = 0.11) or d an increase of the serum C reactive protein (p = 0.84)

Fig. 2

Longitudinal TWEAK serum levels. TWEAK serum level values. We note a global decrease during the first year following onset of disease, but these levels still remained higher compared to controls at 6 months (p = 0.01) and at 12 months (p = 0.06)

Fig. 3

TWEAK serum levels according to presence of disease activity. a The serum levels of soluble TWEAK were significantly increased during relapses, compared to time periods without any relapse (respectively 935 ± 489 pg/mL and 611 ± 292 pg/mL (p = 0.0005)); b The same profile was shown with MRI activity at baseline with serum TWEAK levels of 1421 ± 657 pg/mL in patients who present gadolinium enhancement compared to 975 ± 382 pg/mL in case of absence of gadolinium enhancement (p = 0.02)

Fig. 4

TWEAK MTR. TWEAK serum levels at baseline according to magnetization transfer ratio (MTR) at baseline (a) and at 1 year (b) in white and gray matter. No correlation was evidenced at any time and with any brain tissue

Fig. 5

TWEAK serum levels according to gadolinium enhancement. For 3 patients, baseline TWEAK serum levels were particularly elevated and were superior to the highest standard of the TWEAK ELISA calibration curve (> 2000 pg/mL). The brain MRI (T1 after gadolinium infusion) are presented at baseline and 1 year. TWEAK serum levels at 1 year are also reported