CSF macrophage migration inhibitory factor levels did not predict steroid treatment response after optic neuritis in patients with multiple sclerosis

Abstract

Glucocorticoid (GC) refractory relapses in patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS), who are in potential need of treatment escalation, are a key challenge in routine clinical practice. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be an endogenous counter-regulator of GC, and potentiates autoimmune-mediated neuroinflammation. In order to evaluate whether MIF levels are elevated in the cerebrospinal fluid (CSF) of MS patients (CSF-MIF), and whether they are higher still during a GC refractory relapse, we compared CSF-MIF concentrations of CIS/MS patients with acute optic neuritis as their first inflammatory episode (ON, n = 20), CIS/MS patients with a stable disease progression/without relapse (CIS/MS w/o, n = 18), and healthy controls (HC, n = 20) using ANOVA. Mean CSF-MIF concentrations in CIS/MS w/o patients were significantly higher than in ON patients and HCs, whereas ON patients and HCs did not differ. A subgroup analysis of the ON group revealed 10 patients to be responsive to GC-treatment (GC-ON) and 10 patients refractory under GC-treatment (rGC-ON). However, mean CSF-MIF concentrations did not differ between GC-ON and rGC-ON cases. We therefore conclude that MIF is not suitable for distinguishing GC responders from non-responders in a group of patients with acute optic neuritis, but it rather mirrors the ongoing inflammation in long-term MS disease progression.

Pro- and Anti-Inflammatory Properties of Interleukin in Vitro: Relevance for Major Depression and Human Hippocampal Neurogenesis

“…This is consistent with other studies showing that IL6 can either not change or enhance neuronal differentiation and that these findings are dependent on its concentration ( Johansson et al, 2008 ; Islam et al, 2009 ; Zonis et al, 2013 ; Borsini et al, 2015 ). Similarly, when cells are exposed to low concentrations of IL6 (1 pg/mL) together with low concentrations of IL1β (1 pg/mL) or MIF (10 pg/mL), as found in healthy individuals ( Lindqvist et al, 2009 ; Pawlitzki et al, 2018 ), we do not observe any changes in neurogenesis. In contrast, high concentrations of IL6 (5 pg/mL) with either IL1β (10 pg/mL) or MIF (300 pg/mL), as found in depressed patients ( Piletz et al, 2009 ; Hestad et al, 2016 ; Kranaster et al, 2018 ; Tsuboi et al, 2018 ), decrease dramatically the percentage of newly generated neurons compared not only with low concentrations of the same combination of cytokines but also with the cytokines alone.…”

“…—Across the experiment described below, we have used a range of concentration of cytokines based on the existing literature. Specifically, we used low and high concentrations of IL1β (1, 5 pg/mL), TNF-α (1, 10 pg/mL), MIF (10, 300 pg/mL), and IL6 (1, 5 pg/mL), as found in blood and CSF of, respectively, healthy individuals ( Lindqvist et al, 2009 ; Pawlitzki et al, 2018 ) and depressed patients ( Piletz et al, 2009 ; Hestad et al, 2016 ; Kranaster et al, 2018 ; Tsuboi et al, 2018 ). Moreover, being guided by concentrations found in blood and CSF of healthy individuals or depressed patients exposed to interventions resembling anti-inflammatory conditions ( Raison et al, 2018 ), as well as by a dose-response curve performed on our cellular model, we selected IL6 50 000 pg/mL as the most representative “anti-inflammatory” concentration of IL6.…”

Upregulated Expression of Macrophage Migration Inhibitory Factor, Its Analogue D-Dopachrome Tautomerase, and the CD44 Receptor in Peripheral CD4 T Cells from Clinically Isolated Syndrome Patients with Rapid Conversion to Clinical Defined Multiple Sclerosis

“…The reason for the discrepancies is not known but may possibly depend on the relatively low number of patients and different ethnicities. It is more difficult to compare the reasons for the discrepancies between our present analysis and the study by Pawlitzki and coworkers [26], as they measured MIF levels in CSF, while we studied peripheral CD4 + T cells. Different cells, including glial cells and B cells, may contribute to the intrathecal production of MIF.…”

“…It is worth mentioning that the CSF levels of MIF have also been studied with divergent results in ON associated with MS. While one study found that CSF levels of MIF in these patients were even higher than those observed in MS relapses [25], the other observed lower levels of MIF in CSF samples of patients with MS-associated ON as compared to MS patients with stable RR-MS [26]. The reason for the discrepancies is not known but may possibly depend on the relatively low number of patients and different ethnicities.…”