Tout savoir sur la sclérose en plaques
Defining multiple sclerosis
Multiple sclerosis is an immune system disorder that secondarily causes focal inflammatory lesions ("plaques") in the central nervous system (CNS) and degeneration, induced by this inflammation, of various nerve pathways with destruction of nerve cells (neurons) and their extensions (axons). It is therefore a 'clash' between the two most complex biological systems in the human body, the immune system on the one hand and the CNS on the other.
A global dysregulation of the immune system
Our immune system is a highly complex network of cells and proteins. Its raison d'être is to defend our body against external aggression, in particular bacterial, viral and parasitic infections (anti-infectious immunity). It must also defend us against cancer cells that are no longer normal cells in our body (anti-tumour immunity). If our immune system is disrupted for one reason or another and sets off a self-aggressive reaction against organs in our own body, we speak of autoimmune diseases. Although the exact cause of MS is still not known, it is now considered to be an autoimmune disease of the CNS, which destroys the myelin sheath and/or the cells that produce it (oligodendrocytes), and in some cases, the nerve fibres inside this sheath. The myelin sheath is made up of several spiral coils of a membrane in direct continuity with the membrane of the oligodendrocyte. On the one hand, it has a protective and insulating function, and on the other, it ensures the rapid conduction of electrical nerve impulses.
The immune system comprises two subsets: an "innate" immune system composed of blood monocytes, macrophages and microglia (macrophages specific to the CNS), which is not specific to a particular target, and the "adaptive" immune system composed essentially of lymphocytes specific to a particular antigen. Humans have 490 billion lymphocytes, of which 10 billion circulate in the blood, 190 billion are located in the lymph nodes and 290 billion "patrol" the body's various organs. Under normal circumstances, very few lymphocytes are present in the brain, which is protected by a "barrier" ("blood-brain barrier"). To cross this barrier, the lymphocyte must be "activated", which is the case for the lymphocytes present in the plaques, meninges and cerebrospinal fluid (CSF) of MS patients. We still don't know where this abnormal, unregulated activation occurs. Is it in the lungs? in the cervical lymph nodes ? in the intestinal mucous membrane ? An important fraction of these cells, T lymphocytes, can recognise myelin structures and play a key role in initiating the inflammatory process that leads to myelin destruction. Another group, B lymphocytes, can concurrently activate T lymphocytes and make various antibodies. Some of these antibodies can attack specific myelin structures and also play a role in demyelination. These antibodies are decisive for the diagnosis when they appear as "oligoclonal bands" in the CSF, as these bands are present in 95% of MS patients (see Diagnosis of MS).
Autoimmune T lymphocytes that do not recognise their own myelin and regard it as a "foreign" body are also present in anyone without MS. In this case, they do not cause any lesions or symptoms, because other lymphocytes, regulatory T and B lymphocytes, prevent them from becoming active and proliferating. In MS, this mechanism fails for reasons that are still unknown, and there is therefore a "break in tolerance". It is also possible that T lymphocytes are "tricked" by fragments of infectious agents that strongly resemble myelin proteins. The result is a "cross-reactive" immune response against both the initial infectious agent and the myelin sheath, through "molecular mimicry". This is still only a working hypothesis. The use of regulatory T lymphocytes is an area of research in cell therapy. It should also be emphasised that this overall dysregulation of the immune system in MS does not alter its protective function against common infections, nor does it increase the risk of cancer.
An inflammatory disease of the central nervous system
Once activated, autoimmune B and T lymphocytes cross the blood-brain barrier and enter the CNS. It is in the small veins that blood flow is slowest and that lymphocytes cling to their walls before passing inside the nerve tissue. Magnetic Resonance Imaging (MRI) can sometimes show this central vein in the middle of a plaque. The entire CNS is affected: the meninges, the neurons of the cerebral cortex and the neurons of the deep nuclei (thalamus and basal ganglia), the white matter which contains the majority of myelinated nerve fibres, the cerebellum, the brainstem, the spinal cord and the optic nerves (which are an integral part of the CNS). When the activated T cell recognises its target in the brain, it releases molecules called cytokines, which increase the inflammatory response and cause other lymphocytes and huge numbers of monocytes to enter the brain. These monocytes are transformed into activated macrophages in the same way that microglial cells are activated. The best-known cytokines are interferon gamma and interleukin 17. Other cytokines stimulate enzymes that destroy the myelin sheath. The same phenomena can occur with autoimmune B lymphocytes. This escalation process can be slowed or blocked by factors that inhibit inflammation. One of these inhibitory cytokines is interferon beta, which is an antagonist of interferon gamma and has been widely used in the treatment of MS.
Inflammation is localised mainly in the white matter of the CNS. This is made up of the extensions of the nerve cells themselves, the neurons, which make up the grey matter. An estimated 100 billion neurons and their extensions, which can be very long and are called "axons", link the nerve cells together. Electrical signals travel along the axons carrying information between the different nerve cells. The myelin sheath allows nerve impulses to be conducted very quickly, and economically in terms of energy, at speeds of up to 60 metres/second. Inflammation leads to demyelination and this demyelinated area forms a "plaque" with relatively well-defined contours. Electrical impulses travel through them at a slower rate, with the conduction velocity dropping by up to 10% of the normal rate, and this is how certain symptoms of the disease appear and persist. Three types of plaques can be distinguished: active plaques, containing numerous lymphocytic inflammatory cells and macrophages digesting myelin debris, visible on MRI after injection of contrast medium, caused by the invasion of inflammatory cells of blood origin; chronic active plaques, whose centre is devoid of inflammatory cells but whose periphery is composed of activated macrophages which continue to destroy and digest myelin debris; these plaques continue to enlarge progressively in a centrifugal manner and no longer capture the contrast medium, the inflammation being restricted to the CNS; chronic inactive plaques without inflammatory cells, purely cicatricial, "sclerosed" following the hypertrophy of astrocytes which fill the void left by the destruction of the myelin sheaths and often also, the axons.
The cerebral cortex , which is essentially composed of neurons, nevertheless also contains nerve fibres surrounded by myelin, but less compact and numerous than in the white matter. They can also be destroyed in MS, and so there are also "cortical" plaques. Some are located directly beneath the innermost meningeal layer, known as the pia mater. In the latter case, inflammatory meningeal foci are observed nearby, containing numerous lymphocytes of blood origin which have become "resident" in the CNS.
A neurodegenerative disease caused by focal inflammation with repercussions at a distance
It was long thought that demyelination was the most important process in the disease and that the destruction of neurons and axons only occurred late in the course of the disease. Today, it is certain that nerve extensions can be injured ("transected") A significant reduction in the number of neurons is at times observed in cortical plaques as well as in apparently normal grey matter. This neuronal and axonal loss is responsible for the increase of disability in the progressive phase of the disease, and is the cause of irreversible neurological sequelae. It also causes an excessive reduction in cerebral volume, of 0.5 to 1% per year, greater than the annual reduction of 0.2 to 0.4% observed in normal subjects. This cerebral atrophy is significantly correlated with atrophy of the retina, the thickness of which decreases. In ophthalmology, this thickness can be measured using Optical Coherence Tomography (OCT). It is therefore a very widespread and general phenomenon. In addition to overall brain atrophy, the disease can cause focal atrophy of certain brain structures, in particular the thalamus (an important relay for nerve bundles between the spinal cord and the cortex and an "activator" of the cerebral cortex), the corpus callosum (which contains all the nerve fibres linking the right and left hemispheres together) and the spinal cord. Atrophy of the latter is secondary to damage to the motor and sensory pathways it contains, and is strongly correlated with patients' level of disability.
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