Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis

Abstract

In the majority of patients multiple sclerosis starts with a relapsing remitting course (RRMS), which may at later times transform into secondary progressive disease (SPMS). In a minority of patients the relapsing remitting disease is skipped and the patients show progression from the onset (primary progressive MS, PPMS). Evidence obtained so far indicate major differences between RRMS and progressive MS, but no essential differences between SPMS and PPMS, with the exception of a lower incidence in the global load of focal white matter lesions and in particular in the presence of classical active plaques in PPMS. We suggest that in MS patients two types of inflammation occur, which develop in parallel but partially independent from each other. The first is the focal bulk invasion of T- and B-lymphocytes with profound blood brain barrier leakage, which predominately affects the white matter, and which gives rise to classical active demyelinated plaques. The other type of inflammation is a slow accumulation of T-cells and B-cells in the absence of major blood brain barrier damage in the connective tissue spaces of the brain, such as the meninges and the large perivascular Virchow Robin spaces, where they may form aggregates or in most severe cases structures in part resembling tertiary lymph follicles. This type of inflammation is associated with the formation of subpial demyelinated lesions in the cerebral and cerebellar cortex, with slow expansion of pre-existing lesions in the white matter and with diffuse neurodegeneration in the normal appearing white or gray matter. The first type of inflammation dominates in acute and relapsing MS. The second type of inflammation is already present in early stages of MS, but gradually increases with disease duration and patient age. It is suggested that CD8⁺ T-lymphocytes remain in the brain and spinal cord as tissue resident cells, which may focally propagate neuroinflammation, when they re-encounter their cognate antigen. B-lymphocytes may propagate demyelination and neurodegeneration, most likely by producing soluble neurotoxic factors. Whether lymphocytes within the brain tissue of MS lesions have also regulatory functions is presently unknown. Key open questions in MS research are the identification of the target antigen recognized by tissue resident CD8⁺ T-cells and B-cells and the molecular nature of the soluble inflammatory mediators, which may trigger tissue damage.

Keywords: demyelination; inflammation; neurodegeneration; primary progressive MS; relapsing remitting MS; secondary progressive MS.

Figure 1

Active Lesions in early MS (acute and RRMS). (A) The dominant pathology in early MS is the presence of focal confluent demyelinated lesions in the white matter, many of them being in the stage of activity; section of a patient with acute multiple sclerosis, stained for myelin by immunohistochemistry for proteolipid protein. Magnification bar: 1 mm. (B) The classical active lesions in early MS develop around a central vein with inflammatory infiltrates, composed of CD8⁺ T-cells (red), CD20 positive B-cells (green), and few plasma cells (blue). While B-cells and plasma cells mainly remain in the perivascular space, the CD8⁺ T-cells also diffusely infiltrate the lesion parenchyme. The lesion (blue) is massively infiltrated by macrophages. Many of the lymphocytes are in the process of passing the vessel wall and this is associated with profound blood brain barrier leakage. This results in profound edema, which expands beyond the area of active demyelination (light blue). (C–E) Myelin staining (immunocytochemistry for proteolipid protein) shows patchy areas of active demyelination, which is associated with dense infiltration of the tissue by macrophages (D,E). (F, G) Immunohistochemistry for the T-cell marker CD8 shows perivascular accumulation of T-cells, and their diffuse infiltration of the lesion parenchyme. (H) The perivascular inflammatory infiltrates contain numerous CD20⁺ B-lymphocytes. (I,J) Staining for IgG reveals massive leakage of the blood brain barrier and only a small number of IgG containing plasma cells in the perivascular space (I); the profound blood brain barrier leakage is also reflected by extensive leakage of fibrinogen through the inflamed vessels (J). (K) A subset of macrophages expresses the activation marker CD163, a feature which is typically found in active MS lesions. The magnification bars in the figures (C,G,I) represent 100 μm. Similar histological images as shown in this figure have been previously published. Structure of the lesions: Frischer et al. (46); Inflammatory reaction: Frischer et al. (47); Machado Santos et al. (37); Microglia and macrophages: Zrzavy et al. (38); Fibrin and blood brain barrier injury: Hochmeister et al. (48).

Figure 2

Inflammatory reaction in the brain of patients with progressive MS and its relation to active demyelination and neurodegeneration. The inflammatory reaction in the brain of patients with progressive MS is mainly seen in the large connective tissue spaces of the meninges and the periventricular Virchow Robin spaces. These inflammatory sites mainly contain CD8⁺ T-cells, a major component of CD20⁺ B-cells and a variable number of plasma cells and may in their most severe manifestations become organized in structures with features of tertiary lymph follicles (green dots). In addition there are perivascular cuffs mainly composed of CD8⁺ T-cells, which are more broadly dispersed within the white matter of the brain (red dots). Inflammation with T-cells, B-cells and Plasma cells (green dots) is associated with slow expansion of demyelinated lesions, defined by a rim of activated microglia cells, which in part contain early myelin degradation products in the cortex and the white matter (thick blue lines). Active demyelination and diffuse tissue injury occurs at a distance from the lymphocytic infiltrates and may, thus, be propagated by a soluble demyelinating or neurotoxic factor. Inactive plaques (thin green lines) can still be centered by a vein with a dominant infiltrate by CD8⁺ T-cells (red dots).

Figure 3

Slowly expanding lesions in the progressive stage of MS in the cortex and the white matter. (A) Active cortical lesions are associated with inflammatory infiltrates in the meninges, which are composed of CD8⁺ T-cells (red), CD20⁺ B-cells (green) and plasma cells (blue). Active demyelination occurs at a distance of the inflammatory infiltrates and is associated with activated microglia (blue lesion rim). The lesions gradually expand from the pial surface of the cortex toward the depth of the gray matter. Lymphocyte infiltrates are rare or completely absent in the cortical tissue and in particular at the zone of active demyelination. It is suggested that the inflammatory infiltrates in the meninges produce a soluble factor, which induces demyelination and neurodegeneration either directly or indirectly through microglia activation (arrows). (B) In slowly expanding lesions in the white matter T-cell, B-cell and plasma cell infiltrates are present in the large perivascular Virchow Robin spaces. Active demyelination and neurodegeneration occurs at a distance and is associated with microglia activation. Also in these lesions it is suggested that demyelination and neurodegeneration is driven by a soluble factor, produced by the perivascular lymphocytes or plasma cells (arrows). (C–F) Active cortical lesion in a patient with progressive MS. Subpial myelin is completely lost in an area with meningeal inflammation (C); CD8⁺ T-cells are present in the meningeal infiltrates, but do not enter the cortical parenchyme (D); The meningeal infiltrates also contain IgG positive plasma cells (E), there is however no indication of IgG leakage from the vessels into the tissue, suggesting an intact blood brain barrier. Activated microglia and macrophages are seen at the site of active demyelination in the depth of the gray matter (F). (G,H) Slowly expanding lesion in the white matter of a patient with progressive MS. The inactive plaque center contains vessels with perivascular cuffs of lymphocytes but the active demyelination at the lesion edge is associated with a rim of activated microglia (G,H). Lymphocytes, such as for instance CD8⁺ T-cells and B-cells are present in the large perivascular space of the vessels, but there is little or no infiltration into the lesion parenchyme (I,J). No fibrinogen leakage is observed around inflamed vessels, indicating intact blood brain barrier function (K). Magnification bar representative for all images: 100 μm. Similar histological images as shown in this figure have been previously published. Structure of the lesions: Frischer et al. (46); Inflammatory reaction: Frischer et al. (47); Machado Santos et al. (37); Microglia and macrophages: Zrzavy et al. (38); Fibrin and blood brain barrier injury: Hochmeister et al. (48).