The pathogenesis of multiple sclerosis: a series of unfortunate events

Abstract

Multiple sclerosis (MS) is characterized by the chronic inflammatory destruction of myelinated axons in the central nervous system. Several ideas have been put forward to clarify the roles of the peripheral immune system and neurodegenerative events in such destruction. Yet, none of the resulting models appears to be consistent with all the experimental evidence. They also do not answer the question of why MS is exclusively seen in humans, how Epstein-Barr virus contributes to its development but does not immediately trigger it, and why optic neuritis is such a frequent early manifestation in MS. Here we describe a scenario for the development of MS that unifies existing experimental evidence as well as answers the above questions. We propose that all manifestations of MS are caused by a series of unfortunate events that usually unfold over a longer period of time after a primary EBV infection and involve periodic weakening of the blood-brain barrier, antibody-mediated CNS disturbances, accumulation of the oligodendrocyte stress protein αB-crystallin and self-sustaining inflammatory damage.

Keywords: EBV; MOG; multiple sclerosis; αB-crystallin.

Graphical Abstract

Figure 1.

EBV infection of B cells leads to the establishment of an αB-crystallin-reactive immune repertoire in humans. EBV infection of B cells leads to the intracellular accumulation of the stress protein αB-crystallin that counteracts virus-induced apoptosis. When EBV-derived antigens are subsequently presented to T cells, αB-crystallin-derived epitopes are presented by B cells along with viral epitopes. Since the protein is not expressed in human thymus, potentially reactive T cells that have escaped deletion become activated and form an αB-crystallin-reactive memory T-cell repertoire. They also provide help to B cells that mature into plasma cells which produce antibodies not only against EBV antigens but also against αB-crystallin. Periodic reactivation of the latent EBV infection supports this memory immune repertoire for life (for further details see ref 15; Figure created with Biorender).

Figure 2.

Key elements in the induction of αB-crystallin immune reactivity by EBV. By inducing de novo expression of αB-crystallin in B cells (A) and its subsequent HLA-DR-restricted presentation to T cells. EBV not only activates an immune repertoire against its own viral antigens but also against αB-crystallin. Note how different αB-crystallin-specific T cell lines respond to EBV-infected B cells even before their specific antigen has been exogenously added to the culture (B). Human peripheral blood mononuclear cells frequently contain up to 5% of CD45RO memory T cells that release IFN-γ in response to αB-crystallin (C). This population contains both CD4⁺ and CD8⁺ T cells in variable ratios. Originally published in The Journal of Immunology. Van Sechel et al 1997. EBV-induced expression and HLA-DR-restricted presentation by human B cells of alpha B-crystallin, a candidate autoantigen in multiple sclerosis. J Immunol. 1999 Jan 1;162(1):129-35. PMID: 9886378. Copyright © [1997] The American Association of Immunologists, Inc.

Figure 3.

Drainage of CNS antigens to deep cervical or lumbar lymph nodes is the most likely pathway for the generation of the peripheral anti-CNS antibodies that are found in all adult humans. When cells or tissues within the CNS are subjected to turnover or damage, molecular debris is carried off by the lymphatic system and collected in deep cervical or lumbar lymph nodes. CNS debris in these secondary lymphoid organs will activate resident B and T cells. This likely leads to the accumulation over time of self-reactive T and B cells as well as self-reactive antibodies in the periphery. The immune repertoire thus generated contains antibodies against ubiquitous cellular proteins as well as proteins that are selectively expressed within the CNS (Figure created with Biorender).

Figure 4.

By inducing release of inflammatory cytokines, peripheral inflammatory events may temporarily weaken the blood-brain barrier at certain locations. This will promote trafficking into the CNS of CNS-reactive antibodies and B cells. Peripheral inflammatory events including viral infections lead to temporarily increased serum levels of cytokines such as IFN-γ, TNF-α, and IL-6 that will increase the permeability of the BBB. Especially in regions where the BBB is already relatively permeable under normal conditions, serum antibodies and the B cells that can produce them will thus gain easier access to the CNS than normal. The latter can even go on to form aggregates that persist in the CNS (see also Fig. 6). Among the antibodies entering the CNS will be myelin-reactive ones such as MOG-reactive antibodies (Figure created with Biorender).

Figure 5.

Myelin-reactive antibodies such as those against MOG trigger oligodendrocyte stress. This subsequently results in the release of exosomes containing the stress protein αB-crystallin. Antibodies that bind to the oligodendroglial transmembrane protein MOG trigger membrane perturbations and intracellular changes including stress. To counteract apoptosis, oligodendrocytes accumulate intracellular αB-crystallin which is subsequently also secreted as exosome cargo (Figure created with Biorender).

Figure 6.

Myelin-reactive antibodies induce oligodendroglial αB-crystallin which, in turn, triggers a protective and tolerizing type I interferon-like response in microglia. Exosomes containing αB-crystallin that are released by antibody-stressed oligodendrocyte activate surrounding microglia via CD14 and TLR2. The protective type I interferon-like response this induces will cause microglia to cluster and it promotes repair and immunological tolerance. It also leads to the release of chemokines that stimulate leucocyte recruitment. Collectively, the unique cocktail of mediators produced by activated microglia and infiltrated leucocytes will promote the formation of B-cell aggregates and ectopic follicles that thus become a persistent local source of antibodies including OCBs (Figure created with Biorender).

Figure 7.

Memory T cells against αB-crystallin cause derailment of the process. When sufficient numbers of αB-crystallin-reactive T cells encounter B cells within the CNS that present their target antigen at a sufficiently high concentration, things will go wrong. B cells lack CD14 and, therefore, fail to mount the regulatory and immune-suppressive response to αB-crystallin as seen in microglia and macrophages. Instead, they will allow the development of a substantial IFN-γ response by T cells (see Fig. 2C). This response changes everything since IFN-γ reprograms TLR signaling pathways in microglia and macrophages. Their originally protective response to αB-crystallin now changes into a full-blown destructive response, leading to tissue damage. Furthermore, it will cause substantial destabilization of the BBB and active recruitment of leucocytes, adding more fuel to the fire (Figure created with Biorender).

Figure 8.

Therapeutic intervention in MS with αB-crystallin. A significant memory T-cell response against αB-crystallin is a normal part of the human adult immune repertoire. This is illustrated by the proliferative response of CD45RO + memory T cells as measured by dilution of the cellular marker carboxyfluorescein succinimidyl ester (CFSE) in an example assay using fresh blood from a normal healthy adult (A). As many as 3–5% of all memory T cells frequently respond to αB-crystallin in this way. This T-cell response is associated with the production of IFN-γ, as illustrated by another example assay in panel B. Yet, approximately 10-fold higher concentrations of αB-crystallin are required to trigger this T-cell response as compared to the TLR2-mediated response by macrophages that induces IL-10 production. This difference offers a therapeutic concentration window for tolerance induction. As long as the maximum serum concentration of intravenously administered αB-crystallin remains below the threshold for T-cell activation of around 10 μg/mL, benefit can be taken from the tolerizing macrophage response while avoiding the pathogenic IFN-γ response by T cells. Intravenous doses of either 7.5 or 12.5 mg αB-crystallin lead to sub-immunogenic peak serum concentrations of well below 5 μg/mL. After three bimonthly doses at these levels the total number as well as total volume of gadolinium-enhancing MRI lesions in MS patients are significantly suppressed by about 75% (previously published in part by van Noort et al. 2015, Ref. 21).