Multiple Sclerosis as a Syndrome-Implications for Future Management

Abstract

We propose that multiple sclerosis (MS) is best characterized as a syndrome rather than a single disease because different pathogenetic mechanisms can result in the constellation of symptoms and signs by which MS is clinically characterized. We describe several cellular mechanisms that could generate inflammatory demyelination through disruption of homeostatic interactions between immune and neural cells. We illustrate that genomics is important in identifying phenocopies, in particular for primary progressive MS. We posit that molecular profiling, rather than traditional clinical phenotyping, will facilitate meaningful patient stratification, as illustrated by interactions between HLA and a regulator of homeostatic phagocytosis, MERTK. We envisage a personalized approach to MS management where genetic, molecular, and cellular information guides management.

Keywords: demyelination; innate immunity; multiple sclerosis; pathophysiology; syndrome.

Figure 1

Potential scenarios driving the pathogenesis of MS in which homeostatic interactions between oligodendroglia and the adaptive and innate immune systems break down, leading to inflammatory demyelination, and eventually to neurodegeneration. (A) In Scenario 1, exogenous antigen is processed in peripheral lymphoid tissue and presented to naïve T cells via MHC Class II. A small proportion of the activated T-effector cells traffic through the CNS where some turnover of neural cell macromolecules, including myelin proteins, occurs. Those molecules are either degraded by the innate immune system or are presented at a basal level by antigen-presenting cells (APCs), principally microglia but potentially also oligodendrocytes and their progenitors. Where the exogenous antigen exhibits molecular mimicry to a neural antigen, there is the potential for further activation of inflammatory T cells within the CNS. This leads to a positive feedback loop in which the T-effector cells initiate CNS damage, resulting in increased presentation of neural antigen by APCs and accelerated proliferation and activation of T-effectors locally. (B) In Scenario 2, the processing of neural antigens within APCs becomes corrupted, with the balance shifting from efferocytosis in which molecules are digested, to one in which peptides are presented via MHC class II. Homeostatic mechanisms potentially corrupted include the presentation of phospholipids to the APC by a limited number of cell surface receptors, including MERTK and its ligands proteins and Gas6. MERTK signaling primes the cell to efferocytosis as does the intracellular protein Rab7, which activates lysosomal induced molecular degradation rather than antigen presentation. In this scenario, microglia both have an initial pathogenic role and activate naïve T cells that normally transit through the CNS and to draining cervical lymph nodes in an immune surveillance role, but with potential for reactivity against neural antigens once homeostasis is disrupted. (C) In Scenario 3, pathology intrinsic to oligodendrocytes results in the presentation of neuronal antigens by APCs, including microglia and potentially oligodendroglia. The initial pathology is an oligodendrocytopathy with acceleration of disease driven via activation of microglia and eventually of circulating T cells. (D) Independent of the initiating event, breakdown in homeostatic interactions within the CNS ultimately leads to relatively stereotyped pathology characterized by oligodendrocyte loss, demyelination, and axonal degeneration.