Increased Expression of Ephrins on Immune Cells of Patients with Relapsing Remitting Multiple Sclerosis Affects Oligodendrocyte Differentiation

Abstract

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed in the central nervous system. The degree of repair through oligodendrocyte regeneration and remyelination is insufficient. Ephrins are membrane-bound ligands activating tyrosine kinase signaling proteins that are known to have an inhibitory effect on oligodendrocyte regeneration. In this study, we examined the expression of ephrins on immune cells of 43 patients with relapsing-remitting (RR) MS compared to 27 matched healthy controls (HC). We found an increased expression of ephrin-A2, -A3 and -B3, especially on T cell subpopulations. We also showed overexpression of ephrins on immune cells of patients with RR-MS that increases the forward signaling pathway and that expression of ephrins on immune cells has an inhibitory effect on the differentiation of oligodendrocyte precursor cells (OPCs) in vitro. Our study findings support the concept that the immune activity of T cells in patients with RR-MS has an inhibitory effect on the differentiation capacity of OPCs through the expression and forward signaling of ephrins.

Adeno‐Associated Virus Type 5 Infection via PDGFRα Is Associated With Interstitial Lung Disease in Systemic Sclerosis and Generates Composite Peptides and Epitopes Recognized by the Agonistic Immunoglobulins Present in Patients With Systemic Sclerosis

“…For example, it has recently been reported that Epstein-Barr virus (EBV) infection dramatically increases the odds of developing multiple sclerosis, 47 and while this has been attributed to molecular mimicry between EBV and the glial cell adhesion molecule (GlialCAM) that is the target of autoantibodies, 48,49 it can also be speculated that the GlialCAM peptide(s) might be able to form a complex with viral proteins and the entry receptor (Eph and Eph-receptor binding proteins, ephrins). 50 In conclusion, the results from the study presented here point to a new understanding of some aspects of the pathogenesis of SSc and autoimmune diseases that could have diagnostic and therapeutic implications to assess with subsequent work.…”

Discovering Root Causal Genes with High Throughput Perturbations

“…Prior research has also shown that EPH-ephrin signaling is more prevalent in relapsing-remitting multiple sclerosis than in other subtypes of the disease 44 . EPH-ephrin signaling survived FDR correction in our analysis (Figure 3 (c)).…”

Lysophosphatidic acid signaling via LPA6: A negative modulator of developmental oligodendrocyte maturation

“…Changes in transcriptional regulation are thought to be linked to modifications in OLG heterogeneity (Falcão et al, 2018; Jäkel et al, 2019) and inefficiencies in OLG maturation and myelin repair (Chang et al, 2002; Duncan et al, 2017; Kuhlmann et al, 2008). As cause for such dysregulated gene expression in OLGs, recent evidence points to the actions of extrinsic factors rather than intrinsic OLG defects (Golan et al, 2021; Kirby et al, 2019; Mozafari et al, 2020; Saraswat et al, 2021; Starost et al, 2020). Thus, targeting druggable signaling pathways with the capacity to modulate gene expression profiles associated with OLG maturation has emerged as a promising approach toward promoting repair of the myelin sheath in MS (Angelini et al, 2021; Gaesser & Fyffe‐Maricich, 2016; Göttle et al, 2019; Green et al, 2017; Jeffries et al, 2016, 2021; Lecca et al, 2020; Mausner‐Fainberg et al, 2021; Mierzwa et al, 2013; Petersen et al, 2021; Rajendran et al, 2021; Roggeri et al, 2020; Skinner & Lane, 2020; Thümmler et al, 2019; Wang et al, 2020; Welliver et al, 2018).…”

“…As cause for such dysregulated gene expression in OLGs, recent evidence points to the actions of extrinsic factors rather than intrinsic OLG defects (Golan et al, 2021;Kirby et al, 2019;Mozafari et al, 2020;Saraswat et al, 2021;Starost et al, 2020).…”