Innovations In Clinical Neuroscience

HOTTOP Multiple Sclerosis DEC 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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R E V I E W 17 Hot Topics in Multiple Sclerosis [December 2017] neurodegeneration-provoked inflammation. The inflammation-induced demyelination leads to death loss and subsequent neurodegeneration as in EAE models. 63 APP axonal spheroids indicating transected injured axons are correlated with T and B cell infiltrates in MS lesions. 26 Furthermore, early focal inflammatory lesions are associated with higher density of transected axons than in the later phases of the disease. 64 Moreover, the meningeal inflammation is correlated with the cortical axonal loss and seems to be the driving force for active demyelination, as well as neuronal, axonal, and synaptic destruction, in the cerebral cortex of MS patients. 65 The second hypothesis postulates an autonomous degeneration of oligodendrocytes and myelin followed by MiA and subsequently invasion of inflammatory cells. 66 A combination of both mechanisms where the low-degree inflammation provides constant insult to the susceptible oligodendrocytes or dysfunctional axon–glial unit, like in cases of disturbed iron metabolism, glutamate homeostasis, and mitochondrial dysfunction. 67 Nevertheless, the success of the anti CD20 in slowing the disease progression emphasizes the role of the inflammation, leading to emergence of the first hypothesis as a valid explanation for the neuronal demise in PPMS. 68 SUMMARY OF THE SEQUENCE OF PATHOLOGIC AL EVENTS IN MS Multiple sclerosis is an autoimmune disease involving both autoreactive B and T cells. EBV infection induces formation of autoreactive B cells (BAuto) either through antigen mimicry or through infection of the normally present BAuto-forming apoptosis-resistant active memory BAuto cells (first hit). On the other hand, autoreactive CD4+ T cells (TAuto) are induced by the intestinal microbiome (second hit). Both BAuto and TAuto interact in the peripheral lymphoid tissue. TAuto cells cross the BBB and are further activated by perivascular BAuto cells. B and T cells recognize the neuronal antigens and start an inflammatory reaction, leading to migration of CD8+ cells and macrophages through BBB, as well as activation of the microglial cells and astrocytes, leading to demise of the neurons (first event). The apoptotic neurons and oligodendrocytes release other sequestrated antigens that subsequently will be recognized by B and T cells accentuating the inflammatory reaction (second event) with wide spread low-grade inflammatory process. Other factors like mitochondrial dysfunction, glutamate cytotoxicity, and iron accumulation lead to further demise of neurons (Figure 1). We postulate that different predisposing factors might not only affect the MS course directly but also interact with each other, leading to further complexification of the pathophysiology of the disease. It also might contribute to the determination of the clinical phenotype of the disease by focal accentuation of the inflammatory reaction with the clinical symptoms of an exacerbation (Figure 2). CURRENT AND POSSIBLE FUTURE TREATMENTS Most clinical trials in PPMS w ere disappointing: from methylprednisolone, 69 through glatiramer acetate, 70 rituximab, 71 interferon-beta, 72,73 and at last fingolimod. 74 Lack of efficacy, inappropriate patients' selection, short study period, and non-optimal primary outcome are the major causes of the negative results. 75 The ORATORIO study was the first Phase 3 study to FIGURE 1. Sequence of events in multiple sclerosis. (1) Autoreactive B (BAuto) cells are formed by epitopes mimicry with Epstein–Barr virus (EBV) antigens or through persistent activation of the naturally presence autoreactive B cells through the chronic EBV infection (first hit). (2) Autoreactive CD4+ T (TAuto) cells are formed through antigen mimicry with intestinal flora (second hit). (3) The autoreactive B and CD4+ T cells interact in the peripheral lymph nodes, leading to further activation. (4) After releasing into blood stream, they both cross the blood–brain barrier and interact again in the perivascular space. (5) They recognize the self- antigens sequestrated in the central nervous system and release cytokines to attract other inflammatory cells (macrophages, cytotoxic CD8+) from the blood as well as to stimulate the microglia and astrocytes. (6) and (7) The inflammatory cells attack the neurons and the oligodendrocytes leading to demyelination, neuronal death with release of many sequestrated intracellular antigens (first event). (8) These antigens provoke more B and T cells reaction leading to accentuation of the inflammatory cascade (second event). (9) Other factors like mitochondrial dysfunction, glutamate cytotoxicity, and iron accumulation play an important role in the demise of neurons, especially in primary progressive multiple sclerosis and secondary progressive multiple sclerosis (SPMS).

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