Multiple sclerosis: Immunopathological heterogeneity and its implications

Abstract

MS is the most common autoimmune demyelinating disease of the CNS. For the past decades, several immunomodulatory disease-modifying treatments with multiple presumed mechanisms of action have been developed, but MS remains an incurable disease. Whereas high efficacy, at least in early disease, corroborates underlying immunopathophysiology, there is profound heterogeneity in clinical presentation as well as immunophenotypes that may also vary over time. In addition, functional plasticity in the immune system as well as in the inflamed CNS further contributes to disease heterogeneity. In this review, we will highlight immune-pathophysiological and associated clinical heterogeneity that may have an implication for more precise immunomodulatory therapeutic strategies in MS.

Keywords: precision medicine ⋅ biomarkers ⋅ brain barriers immunotherapy ⋅multiple sclerosis.

Figure 1

Unmet needs of personalized treatment approaches: MS relapse. (Left) MS standard treatment. With the occurrence of new or worsening symptoms of MS (e.g. visual, sensory, motor), further workup and therapy currently follow stereotypic flows and guidelines. Following neurological examination and exclusion of confounding factors (e.g. infections), high dose glucocorticosteroid “pulse therapy” is the current standard of care. If symptoms do not remit, a second, potentially dose‐escalated glucocorticosteroid pulse is administered. Apheresis techniques (plasma exchange/immunoadsorption) are employed in glucocorticosteroid‐resistant cases, not taking into account different sources of heterogeneity that lead to treatment nonresponse (“try and error”). (Right) MS personalized treatment. In a personalized approach, objective and prognostic markers on an individual level would be taken into account for a treatment decision. This marker profile would be informed by the mechanisms associated with heterogeneity in response to GC therapy as discussed in the text. Treatment could consist of different approaches (e.g. glucocorticosteroids, apheresis, new substances) also in combination. It is unclear, if treatment response in acute relapses varies over time, so marker profiles would potentially have to be individually updated to ensure response state during future relapses. Although some current findings will inform further research, at present no such marker profile exists.

Figure 2

Factors that determine heterogeneity of treatment response in MS Individual factors (e.g. genetic background) combined with interindividual heterogeneity of immunopathophysiological changes as detailed in the text. Together they determine response to immunotherapy, which in itself harbors multiple sources of heterogeneity. Finally, societal aspects are relevant both in terms of MS pathophysiology (e.g. environmental risk factors), development of and access to treatment as well as support to cope with the disease. BMI, body mass index.