Gas6/TAM system as potential biomarker for multiple sclerosis prognosis

Abstract

Introduction: The protein growth arrest-specific 6 (Gas6) and its tyrosine kinase receptors Tyro-3, Axl, and Mer (TAM) are ubiquitous proteins involved in regulating inflammation and apoptotic body clearance. Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system leading to progressive and irreversible disability if not diagnosed and treated promptly. Gas6 and TAM receptors have been associated with neuronal remyelination and stimulation of oligodendrocyte survival. However, few data are available regarding clinical correlation in MS patients. We aimed to evaluate soluble levels of these molecules in the cerebrospinal fluid (CSF) and serum at MS diagnosis and correlate them with short-term disease severity.

Methods: In a prospective cohort study, we enrolled 64 patients with a diagnosis of clinical isolated syndrome (CIS), radiological isolated syndrome (RIS) and relapsing-remitting (RR) MS according to the McDonald 2017 Criteria. Before any treatment initiation, we sampled the serum and CSF, and collected clinical data: disease course, presence of gadolinium-enhancing lesions, and expanded disability status score (EDSS). At the last clinical follow-up, we assessed EDSS and calculated MS severity score (MSSS) and age-related MS severity (ARMSS). Gas6 and TAM receptors were determined using an ELISA kit (R&D Systems) and compared to neurofilament (NFLs) levels evaluated with SimplePlex™ fluorescence-based immunoassay.

Results: At diagnosis, serum sAxl was higher in patients receiving none or low-efficacy disease-modifying treatments (DMTs) versus patients with high-efficacy DMTs (p = 0.04). Higher CSF Gas6 and serum sAXL were associated with an EDSS <3 at diagnosis (p = 0.04; p = 0.037). Serum Gas6 correlates to a lower MSSS (r² = -0.32, p = 0.01). Serum and CSF NFLs were confirmed as disability biomarkers in our cohort according to EDSS (p = 0.005; p = 0.002) and MSSS (r² = 0.27, p = 0.03; r² = 0.39, p = 0.001). Results were corroborated using multivariate analysis.

Conclusions: Our data suggest a protective role of Gas6 and its receptors in patients with MS and suitable severity disease biomarkers.

Keywords: Gas6; TAM receptors; biomarker; inflammation; multiple sclerosis.

Figure 1

Distribution of Gas6 and TAM receptor concentrations in serum (A) and CSF (B). Results are shown as medians [IQR]. Spearman’s rank correlation between serum and CSF levels of Gas6 (C), sTyro-3 (D), sAxl ((E), and NFLs (F) concentrations. r², coefficient of correlation; p, p-value.

Figure 2

Association between Gas6 concentration in the serum (A) and CSF (B), sTyro3 concentration in the serum (C) and CSF (D), sAxl concentration in the serum (E) and CSF (F), sMer concentration in the serum (G), NFLs concentration in the serum (H) and CSF (I) and the type of therapy at follow-up visit. Results are shown as medians [IQR]. *p = 0.04, ns, not significant.

Figure 3

Associations between Gas6 levels in the serum and CSF (ng/ml) and < 3 or ≥ 3 EDSS clinical scores on the first visit. *p = 0.04 (A, B). sAxl levels in the serum and CSF (ng/ml) in patients with < 3 or ≥ 3 EDSS clinical scores on the first visit. *p = 0.037 (C, D). Associations between NFLs levels in the serum and CSF (pg/mL) and < 3 or ≥ 3 EDSS clinical scores on the first visit. **p = 0.005, **p = 0.002 (E, F). Results are shown as medians [IQR]. ns, not significant.

Figure 4

Spearman’s correlation between MSSS and Gas6 levels in the serum and CSF (A, B), TAM receptors levels in the serum and CSF (C–G), and NFLs levels in the serum and CSF (H, I). r² = coefficient of correlation, p = p-value.