The Translatability of Multiple Sclerosis Animal Models for Biomarkers Discovery and Their Clinical Use

Abstract

Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system which is characterized by demyelinating lesions and axonal damage. MS is a complex disease characterized by important pathophysiological heterogeneity affecting the clinical appearance, progression and therapeutic response for each patient. Therefore, there is a strong unmet need to define specific biomarkers that will reflect the different features of the disease. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for the study of MS, as it resembles the pathological features of human MS in many aspects and has allowed for the elucidation of pathogenesis pathways and the validation of certain targets for MS therapies. In this review, we discuss clinically relevant MS molecular biomarkers, divided into five groups based on the key pathological hallmarks of MS: inflammation, blood-brain barrier disruption, myelin and axonal damage, gliosis and, ultimately, repair mechanisms. To address the feasibility of translation between the animal model and human disease, we present an overview of several molecular biomarkers of each category and compare their respective deregulation patterns. We conclude that, like any disease animal model, EAE models can sometimes fail to mimic the entire spectrum of human disease, but they can nonetheless recapitulate the disease's primary hallmarks. We show that the EAE model is a valuable tool for understanding MS physiopathological mechanisms and for identifying biomarkers fundamental for drug development.

Keywords: EAE; animal models; biomarkers; multiple sclerosis.

Figure 1

Schematic representation of inflammation in MS pathology. BBB: Brain Blood Barrier, BCR: B-cell receptor; CXCL13: Chemokine (C-X-C Motif) Ligand 13, CXCR5: Chemokine (C-X-C Motif) receptor type 5, IL-17: Interleukin 17, IL-17R: Interleukin 17 receptor, LB: lymphocytes B, TCR: T-cell receptor, Th17: T helper 17 cells, OPN: Osteopontin.

Figure 2

Schematic representation of BBB breakdown. ADAMTS13: A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, Member 13, MMP2/9: Metalloproteinase-2 and -9, LB: lymphocytes B, LT CD4⁺: CD4 T lymphocytes, LT CD8⁺: CD8 T lymphocytes, VWF: Von Willebrand factor.

Figure 3

Schematic representation of astrogliosis. GFAP: Glial Fibrillary Acidic Protein, S100b: S100 calcium binding protein B.

Figure 4

Schematic representation of myelin and axonal damages. BBB: Blood brain barrier, LT CD4⁺: CD4 T lymphocyte, LB: lymphocyte B, MBP: myelin binding protein, MOG: myelin and oligodendrocyte glycoprotein, NFH: neurofilament heavy chain, NFL: neurofilament light chain.

Figure 5

Schematic representation of repair mechanisms mediated by HGF and BDNF. BDNF: Brain-derived neurotrophic factor, c-Met: tyrosine protein kinase Met, HGF: Hepatocyte growth factor, OPC: oligodendrocyte precursor cell, LT CD4⁺: CD4 T Lymphocyte, LTreg: regulatory T lymphocyte, TrkB: tropomyosin receptor kinase B.