Mechanisms underlying progression in multiple sclerosis

Abstract

Purpose of review: In multiple sclerosis, currently approved disease-modifying treatments are effective in modulating peripheral immunity, and coherently, in reducing clinical/radiological relapses, but still, they perform poorly in preventing disease progression and overall disability accrual. This review provides an up-to-date overview of the neuropathology of progressive multiple sclerosis, including a summary of the main mechanisms of disease progression.

Recent findings: Clinical progression in multiple sclerosis is likely related to the accumulation of neuro-axonal loss in a lifelong inflammatory CNS environment (both adaptive and innate) and relative un-balance between damage, repair and brain functional reserve. A critical driver appears to be the T-cell and B-cell-mediated compartmentalized inflammation within the leptomeninges and within the parenchyma. Recent perspective highlighted also the role of the glial response to such lifelong inflammatory injury as the critical player for both pathological and clinical outcomes.

Summary: The neuropathological and biological understanding of disease progression in multiple sclerosis have progressed in the last few years. As a consequence, new therapeutic approaches are emerging outside the modulation of T-cell activity and/or the depletion of B cells.

Conflict of interest statement

Conflicts of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.. Inflammation and tissue injury in multiple sclerosis lesions

a-c: Chronic active lesion in a 41-year old male patient with MS contains prominent inflammation, consistent of CD8+ T-cells (a), CD20+ B-cells (b) and immunoglobulin containing plasma cells (c). While CD8+ T-cells are present in the perivascular space and also diffusely infiltrate the lesion, infiltration by B-cells and plasma cells is largely restricted to the perivascular space. d: Distribution and phenotype of inflammatory cells in newly formed active lesions. In newly formed lesions mainly seen in acute and relapsing MS new waves of T-cells and B-cells enter the brain and spinal cord and this is associated with profound blood brain barrier leakage. Many of the T- and B-cells are activated, but some of them already differentiate into tissue resident memory T-cells and plasma cells. Activated microglia and macrophages are seen throughout the entire lesion, but most numerous at the expanding edge. e: Distribution and phenotype of inflammatory cells in chronic active (slowly expanding) lesions. Such lesions are mainly seen in the (late) relapsing and progressive stage of the disease. The inflammatory reaction is compartmentalized within the brain behind a (partly) closed or repaired blood brain barrier. The CD8+ T-cells dominate. Most of them are tissue resident memory cells in an inactive stage, but these cells show focally restricted activation. Activated T-cells are seen in close contact with B-cells and macrophages/microglia. Besides CD8+ T-cells many B-cells are present and a substantial number of them has differentiated into immunoglobulin containing plasma cells. f-h: Zone of active demyelination at the edge in the same lesion, shown in figures a-c. Immunohistochemistry for proteolipid protein (myelin) reveals a sharp edge of demyelination with some granular myelin degradation products (f). The zone of active demyelination is heavily infiltrated by activated microglia cells and macrophages, expressing NADPH oxidase (p22phox) as a potential source for oxygen radicals (g). The zone of active demyelination shows precipitation of oxidized phospholipids in cells and cell processes as well as in the cytoplasmic granules of macrophages (h). Magnification bar: 100 mm.

Figure 2.. Longitudinal brain MRI features in progressive MS

The case is a 60-year old man with primary progressive MS, EDSS 7.0 and 26 years of disease duration (treated with IFNß-1a between ages 52–57). Longitudinal MRI scans (proton density sequence) clearly show the expansion of supratentorial chronic white matter lesions (red arrows) as well as the progressive brain atrophy with lateral ventricle enlargement. The profiles of the ventricles at age 45 (red dashed line) and age 60 (blue dashed line) are superimposed to the last MRI scan to facilitate the comparison.

Figure 3.. Demyelinated brain lesion distribution on postmortem MRI in progressive MS

The case is a 59-year old man with progressive MS, EDSS 6.5 and 21 years of disease duration (treated with IFNß-1a between ages 49–51). Postmortem MRI scans (gradient echo sequence) of the formalin-fixed brain shows extensive cortical demyelination (yellow asterisks), especially in the depth of the sulci and the hippocampi, and confluent chronic active/slowly expanding lesions (periventricular and leukocortical; red asterisks). Some demyelinated lesions are seen also within the thalamus.

Figure 4.

Hemispheric section from the brain of a chronic progressive MS patient stained for myelin PLP. The absence of staining depicts demyelination and includes white matter lesions (arrows), subpial lesions (arrowheads) and leukocortical lesions (subcortical white matter and cortex, asterisks).