Pre-clinical and Clinical Implications of "Inside-Out" vs. "Outside-In" Paradigms in Multiple Sclerosis Etiopathogenesis

Abstract

Multiple Sclerosis (MS) is an immune-mediated neurological disorder, characterized by central nervous system (CNS) inflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Although autoimmunity, inflammatory demyelination and neurodegeneration underlie MS, the initiating event has yet to be clarified. Effective disease modifying therapies need to both regulate the immune system and promote restoration of neuronal function, including remyelination. The challenge in developing an effective long-lived therapy for MS requires that three disease-associated targets be addressed: (1) self-tolerance must be re-established to specifically inhibit the underlying myelin-directed autoimmune pathogenic mechanisms; (2) neurons must be protected from inflammatory injury and degeneration; (3) myelin repair must be engendered by stimulating oligodendrocyte progenitors to remyelinate CNS neuronal axons. The combined use of chronic and relapsing remitting experimental autoimmune encephalomyelitis (C-EAE, R-EAE) ("outside-in") as well as progressive diphtheria toxin A chain (DTA) and cuprizone autoimmune encephalitis (CAE) ("inside-out") mouse models allow for the investigation and specific targeting of all three of these MS-associated disease parameters. The "outside-in" EAE models initiated by myelin-specific autoreactive CD4⁺ T cells allow for the evaluation of both myelin-specific tolerance in the absence or presence of neuroprotective and/or remyelinating agents. The "inside-out" mouse models of secondary inflammatory demyelination are triggered by toxin-induced oligodendrocyte loss or subtle myelin damage, which allows evaluation of novel therapeutics that could promote remyelination and neuroprotection in the CNS. Overall, utilizing these complementary pre-clinical MS models will open new avenues for developing therapeutic interventions, tackling MS from the "outside-in" and/or "inside-out".

Keywords: animal models; autoimmunity; demyelination; etiopathogenesis; multiple sclerosis.

FIGURE 1

“Inside-Out” model of MS pathophysiology. The “inside-out” model of MS pathogenesis begins with the release of myelin antigens from injured or destabilized myelin to the periphery (1) followed by the presentation of myelin epitopes to (2) and activation of autoreactive T cells (3). Activated autoreactive T cells then migrate into the CNS, are reactivated by CNS-resident APCs (4), and release cytokines leading to direct as well as indirect damage to myelin (5). Additional myelin epitopes released by the primary T cell response induce epitope spreading (6) leading to additional myelin destruction (7).

FIGURE 2

“Outside-In” model of MS pathophysiology. The “outside-in” model of MS pathogenesis begins with activation of myelin-specific T cells in response to a myelin peptide mimic epitope expressed on a pathogenic virus or other microbe exposure (1–2). Activated autoreactive T cells then migrate into the CNS, are reactivated by CNS-resident APCs (3), and release cytokines leading to direct as well as indirect damage to myelin (4). Additional myelin epitopes released by the primary T cell response induce epitope spreading (5) leading to additional myelin destruction (6).