Evaluation of the role of lymphocytes in remyelination and defining the molecular basis for an efficient myelin repair in patients.

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Linking genotypes to MS susceptibility and severity

After the discovery of several susceptibility variants for MS, attempts were made to link the genotype of patients with their phenotype to predict disease course and severity. For instance, patients carrying the (HLA) DRB1*1501 allele show cognitive impairments due to more important neuronal degeneration (Okuda et al., 2009). A recently discovered polymorphism in the oligoadenylate synthetase 1 gene is linked to increased disease activity and relapse frequency in patients carrying the risk allele (O’Brien et al., 2010).
Several other polymorphisms have well established consequences on LT functions: A loss of function on regulatory anti-inflammatory processes is involved in MS susceptibility. For instance, Regulatory T cells (Treg) of patients carrying the risk allele of the CD226 gene showed reduced immunosuppressive capacity and therefore could contribute to a decrease of the peripheral tolerance leading to the survival and the proliferation of autoreactive T cells (Piédavent-Salomon et al., 2015). Mice carrying the risk allele also had a loss of function of Treg cells leading to an exacerbated disability score when Experimental autoimmune encephalomyelinitis (EAE), an animal model of MS, was induced. A gain of function of pro-inflammatory processes is also responsible for MS onset: One of the variants associated to the SLC9A9 gene led to a reduced expression of its mRNA in MS patient carrying this risk allele and this reduction induced an increased expression of IFN-γ by T-cells (Esposito et al., 2015). Mechanistically, a reduced expression of SLC9A9 favors differentiation into T helper 1 (Th1).

North-south gradient of MS prevalence and vitamin D

There is a North-South gradient of the prevalence of MS in the world (Figure 6). Likewise, there is a strong inverse correlation between ultra violet radiation (UV) exposure and risk for MS. In other words, it is likely sun exposure decreases the risk of developing MS.
Vitamin D and its active derivative cholecalciferol and ergocalciferol, has a well described role in calcium metabolism and notably in skeleton remodeling. The main source of Vitamin D in humans is the skin which synthesizes it after exposure to UV. Therefore, there is also a North-South gradient of blood levels of Vitamin D in the world. These phenomena are only correlative and not demonstrated to be causative, but there is an accumulation of clues in the direction of low vitamin D levels as a susceptibility factor for MS (Ascherio et al., 2010; Lucas et al., 2015): Retrospective studies show that in average MS patients had lower vitamin D level in the blood before the disease onset than the general population and people that follow a vitamin D treatment have lower risk of developing MS (Duan et al., 2014; Martinelli et al., 2014). Finally, migration studies show that individuals who have moved from their country of origin to a more southern country have a lower risk of MS (Gale C.R., 1995).
Vitamin D has potent immunomodulatory effects that could explain its protective role for MS (Ascherio et al., 2010; Koch et al., 2013; Prietl et al., 2013). Notably, vitamin D has been shown to increase suppressive properties of Tregs, induce tolerogenic antigen presenting cells, reduce the invasion of macrophages in the CNS during EAE, and foster Th cell differentiation towards the Th2 phenotype which has immunomodulatory properties. In addition, vitamin D levels are lower in MS patients, and there is a correlation between low level of Vitamin D and severity of the disease. However, while vitamin D treatment ameliorated the wellbeing of patients, it did not show any promising effect on disease severity or frequency of relapses.

Symptoms and diagnosis

MS lesions can occur anywhere in the CNS and the symptoms of patients will depend on the function of the neurons affected by demyelination and neurodegeneration. Therefore MS patients can experience a large spectrum of symptoms (Figure 7), from loss of vision to cognitive impairment. The diagnosis of MS is certain when two lesions in the white matter, separated in time (>1month) and in space appears in the CNS. Usually, the lesions are visualized by magnetic resonance imaging (MRI) (Compston and Coles, 2008). Other diagnosis tools are available to the clinicians such as the high concentrations of IgG antibodies and/or oligoclonal bands in the cerebrospinal fluid (CSF), or measurement of evoked potential (visual, brainstem, sensory) which can be slowed down in case of demyelination (Compston and Coles, 2008). In the clinical routine, disease evolution and severity is calculated only taking the walking difficulty into account (Expanded Disability Status Scale or EDSS), or the EDSS weighted by disease duration (Multiple Sclerosis Severity Score or MSSS).

Inflammation, demyelination and neurodegeneration

The hallmark of MS is the presence of several demyelinated plaques disseminated within the CNS. MS lesions were first characterized in the white matter but lesions can also be found in the gray matter of patients. These demyelinating plaques are the consequences of an autoimmune attack against myelin mediated by LT and invading macrophages crossing the BBB and by resident microglia (MIG) (Figure 9). The autoimmune attack occurs because of a failure of suppression of autoreactive T cells and of a dysregulation of the global inflammatory response (Compston and Coles, 2008; Dendrou et al., 2015).


Relapsing phase of MS

MS can be considered as a disease with two phases: The RR phase characterized by a strong inflammation and the progressive phase (including SP and PP) in which neurodegeneration occurs with a decreased presence of inflammation in the CNS.
In RRMS, relapses are triggered by a massive inflammatory attack leading to demyelination. What is causing the immune system to trigger the inflammatory storm during a relapse is not known. Chronic inflammation will induce OL death, leading to chronic demyelination. In this stage of the disease, several gadolinium positive active plaques are found, the vast majority in the white matter. Once the inflammatory storm is over, myelin repair can occur. When this process is efficient, axons do not degenerate and a normal axonal function is restored (Duncan et al., 2009). This process is believed to allow a total or a partial remission in patients . However, axonal death is already present in lesion of RRMS patients in early disease course (Hauser and Oksenberg, 2006), that could explain why the remission is sometimes not total in patients.

Progressive phase of MS

In the progressive phase of MS, there is a chronic and steady axonal loss correlating with disability progression in the patient. The progressive phase is characterized by neuronal death leading to brain atrophy affecting white and grey matter (Fisher et al., 2008; Jacobsen et al., 2014; Lanz et al., 2007; Losseff et al., 1996). Inflammation is less prominent in plaques.
The mechanisms leading from the inflammatory component to the neurodegenerative component are not fully understood and several hypotheses have been proposed: 1) MS is a primary neurodegenerative disorder and the inflammatory processes are not causing axonal death. 2) The inflammation and neurodegeneration are interlinked, and neurodegeneration is the result of chronic demyelination due to inflammatory processes.
The first hypothesis is supported by the fact that MRI studies show subtle changes in the white-matter of patients before the appearance of a lesion and breakdown of the BBB (Filippi et al., 1998). However, experimental and clinical data are arguing for the second hypothesis in which neurodegeneration is driven by inflammation. In EAE, neurodegeneration can be triggered by priming T cell against myelin antigen (Kornek et al., 2000a). In patients, active cortical plaques are always associated with immune cell infiltration (T and B cells) in the meninges and there is a correlation between B cell infiltration and disability progression (Kutzelnigg et al., 2005). Diffuse white matter injury associated with perivascular and parenchymal infiltration of T cells and MIG activation is also found in patients suffering from progressive MS (Prineas et al., 2001). Globally, the view on neurodegenerative processes in progressive MS as being inflammation-independent is unlikely. There is a large amount of diffuse, perivascular and meningeal inflammation mediated by T cell, B cell and substantial MIG activation (Lassmann, 2010). These inflammatory processes are strongly correlated with neuronal death (Frischer et al., 2009).

Table of contents :

Chapter I: Introduction
I. Multiple sclerosis: Etiology and treatments
1. Foreword
2. Myelin
3. Etiology
4. Clinical description & existing treatments
II. Pathophysiology and Immunopathology of MS
1. Inflammation, demyelination and neurodegeneration
2. Role of T cells in MS and animal models
3. Role of B cells in MS and animal models
4. Role of Macrophages and Microglia in MS and animal models
5. MS Lesions
III. Remyelination
1. Forewords
2. Histological description and clinical relevance
3. Mechanisms of remyelination
4. Remyelination heterogeneity: causes of remyelination failure
IV. Aims of the project
Chapter 2: Evaluation of the role of lymphocytes in remyelination and defining the molecular basis for an efficient myelin repair in patients.
I. Introduction
II. Article 1 and contribution
III. Supplementary unpublished results
IV. Patent
Table of contents
Chapter 3: Linking MS susceptibility variants to remyelination capacity
Chapter 4: Discussion and conclusion
I. Role of lymphocytes in remyelination
1. Experimental evidence
2. Cellular mechanisms involved
3. Modeling LT role in remyelination
II. Enhancing endogenous remyelination: acting directly on OPCs
1. Rational
2. Limitations
III. Deciphering patient’s remyelination heterogeneity to determine the prerequisite for efficient myelin repair in MS
1. Involvement of LT in heterogeneity.
2. Capitalizing on patients with high repair capacities to develop innovative therapeutic targets
3. Genetic variants as the root cause
IV. Conclusion
Bibliography :


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