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 15 Hot Topics in Multiple Sclerosis [December 2017] cervical cord atrophy, 12 indicating a possible role in evolving of the disease phenotype. Nevertheless, no loci so far have been associated with a specific clinical subtype like PPMS. Environmental factors. The most important environmental factor is the sun exposure and its subsequent effect on vitamin D deficiency. 13 The role of vitamin D is prominent only in RRMS, where serum levels of vitamin D are low and correlate with relapse rates. 14 PPMS patients have normal levels of vitamin D 15 with no correlation with disability progression. 16 Vitamin D interacts with HLA-DRB1*1501 17 influencing the proliferation, maturation, and function of different immune cells. 15 The above mentioned findings make it tempting to postulate a role of vitamin D in the evolution of the clinical phenotype of MS. Epstein–Barr virus infection. Epstein–Barr virus (EBV) is involved in different pathophysiological aspects of MS; patients with RRMS are more frequently EBV seropositive than controls, and the risk of MS increases in seronegative individuals dramatically after the seroconversion. 18 Delayed primary EBV infection and MS share many epidemiological features like socioeconomic status, latitudinal variation, and effect of migration. 19 Elevated anti-Epstein–Barr nuclear antigen 1 IgG was also found in the PPMS patients and was associated with MRI disease activity. 20 EBV infects B cells, leading to their maturation into latently infected, apoptosis-resistant memory B cells. 21 EBV-infected B cells are found in the meningeal infiltration, perivascularly, WMLs and in cervical lymph nodes in PPMS. 22 EBV involvement in the disease is extensively reviewed by Pender and Burrows. 23 EBV induces autoreactive B cells formation (BAuto) through cross reactivity with some myelin, bystander damage during the immune reaction against EBV infection, immune reaction against crystallin expressed by oligodendrocytes, and at last infection of some naturally present autoreactive B cells, leading to their maturation and initiating the immune cascade in CNS. 23 The immune reaction to EBV infection in healthy older subjects (>50) is characterized by secretion of IFN-γ and IL-6, leading to a chronic inflammatory state with progressive activation of tissue-resident macrophages and monocytes, 24 an immune state similar to PPMS. However, these similarities should be confirmed in further studies. Age. The progressive phase of MS is the result of long-lasting degenerative changes, which appears only when an age threshold is reached and progresses in similar rates. 25 Generally, older patients with MS exhibit less focal inflammation, 26 with more frequent motor, brainstem, and cerebellar manifestations associated with limited recovery capacities in RRMS, 27 making the distinction between incompletely resolving acute attacks and progressive worsening, according to the current definition of relapses, very challenging. Gut microbiome. Gut flora can provoke autoreactive CD4+ formation through antigenic mimicry, mostly with myelin oligodendrocytes glycoprotein or through innate immune signaling. 28 Germ-free EAE mice were protected from the development of inflammatory lesions in brain with marked reduction in Th17 cells. Recolonization resulted in restoration of the Th17 and development of the EAE symptoms. 29 A concrete role of the gut microbiome in PPMS is still unknown. PATHOLOGIC AL CHANGES The predominant lesions in PPMS are slowly expanding lesions with T cells, microglial, and macrophage-associated demyelination in close similar to pattern 1 demyelination. 30 While the involvement of different CD4+ subtypes (Th1, Th17, and Th9) is one of the initial events in MS, 31 the main lymphocytes found in the lesions are CD8+ cells and correlate with the degree of axonal damage. 32 sCD27, a marker of intrathecal inflammation secreted mainly by T cells, is elevated in PPMS. 33 Prominent TFH and Th17 activation in serum of PPMS patients was reported and correlated with the progression rate. 34 Evidences for B cell involvement in PPMS are numerous: the intrathecal IgG production, the detection of B cells within MS lesions, meningeal infiltrate, perivascular space and MS parenchyma, the presence of autoreactive antibodies against myelin and its products, 32 and finally the success of B cell- based therapies in PPMS. 35 B cells are scattered in the meninges in a diffuse manner with tertiary lymphoid follicles formation only in the aggressive form of the disease, with active progressive disease. 36 B- and plasma cells in PPMS lesions correlate with the severity of axonal damage. 26 B cells are pathogenic through multiple pathways, including antigen presentation, cytokines release, and production of the autoantibodies. 37 Their role beyond the synthesis of autoantibodies is confirmed by the fact that highly effective monoclonal anti CD-20 antibodies do not eliminate the long-lasting antibodies producing plasma cells. 37 One example for non- antigen-presenting B cells is the pro- inflammatory granulocyte macrophage colony-stimulating factor (GM-CSF) B cells; through their GM-CSF secretion they induce pro-inflammatory myeloid cell response promoting the release of Th1- and Th17-differentiating cytokines like IL-6 and -12. 38 The discovery of the Breg cells secreting IL-10, IL-35, and TGF-b indicates the complex role of B cells in MS. Breg can restore Th1/Th2 balance, inhibit Th1 and Th17 cell differentiation, and inhibit macrophages. 37 Moreover, the secreted antibodies might play a role in regulating the immune system and inducing remyelination. 39 Phagocytic cells like the macrophages are the most common cells found in the slowly expanding lesions in PPMS. 30 They are derived from blood monocytes and migrate into the CNS after stimulation in the blood. 40 The pro-inflammatory M1 play central role both in the demyelination and axonal damage through reactive oxygen spices, nitric oxide, and glutamate. 40 CNS- infiltrating macrophages were able to induce progressive EAE through sustained

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