MS (Multiple Sclerosis) and Natalizumab

MS or multiple sclerosis is a neurodegenerative disease that affects the central nervous system and subsequently adverse systemic effects throughout the human body. In normal conditions, myelinated neurones work alongside the central nervous system to first receive sensory stimuli from various receptors, as well as act according using efferent nerves. With the effective uptake of Na+ ions and subsequent action potential formation, electrical messages are transmitted throughout the body in regard to sensation, motor co-ordination and general neurological function. However, MS involves the chronic neurodegeneration of these nerves and its symptomology is a result of CNS and neuronal damage. With the central nervous system compromised, signs of MS vary from patient to patient, however with common symptomology including weakness and muscular atrophy, as well as fatigue and lethargy and loss of motor function and balance. As MS directly affects the functioning of the brain and its substituents, neuropsychological symptoms like depression, memory and anxiety are also consistent.

The disease process and aetiology of MS involves destruction of the myelin sheath in nerve fibres that make up neural networks in the brain and spinal cord. This myelin sheath is a protective, fatty insulator that is pivotal for faster signal transduction / transmission as well as faster action potential propagation. With MS, the neurone membrane is damaged, and form random lesions hence the etymology for sclerosis, Greek for scars. These scars manifest on the membrane leaving patches and areas of exposure; the result being ‘demyelination, acute axonal transection, gliosis and subsequent axonal degeneration’. Acute axonal transection refers to destruction of the neurone in a transverse fashion a common repercussion of MS. Another aforementioned consequence of MS involves gliosis; deterioration of glial cells responsible for myelination and healthy neurone function. With no effective medium to transmit electrical impulses, the CNS is not able to receive sensation from afferent neurones as well as act accordingly using efferent neurones. Given the disease process of MS and its destructive nature of neurones, motor function and lapses in cognitive and emotional processes are justified.

Multiple sclerosis is a chronic and systemic disease and its aetiology and causation is unknown, however posits that autoreactive CD8+ lymphocytes launch an inflammatory immune response against oligodendrocyte and other monitoring glial cells that maintain and monitor myelin formation and functionality. Further, Pili et al 2017 also elucidates that it is in fact a genetic predisposition that leads to incorrect T lymphocyte maturation in the thymus organ, where autoreactive lymphocytes are not apoptosised and allowed to mature to perform primary roles in the immune system. In normal conditions, the immune system correctly identifies autoreactivity and autoimmunity in immature T lymphocytes and undergo negative selection in order to free the human body of autoimmune diseases. MS therapy involves mitigating and regulating the transmigration of these autoreactive lymphocytes into the blood-brain barrier via adhesion ligand reception. As research from Legroux and Arbour supports ‘the abundance of immune cells such as T lymphocytes and their products in CNS lesions of MS patients supports the notion that MS is an immune-mediated disorder’.

Natalizumab or commercially referred to as Tysabri, actively blocks the transmigratory process of lymphocytes specifically inhibiting the integrin receptor needed to allow for lymphocytic entry to the CNS and axonal degradation, according to Hutchinson. Natalizumab is an antagonistic humanised monoclonal antibody, when defined is an immunotherapeutic approach that uses identical peptide antibodies against α4 integrin adhesion antigens presented on the surfaces of malignant lymphocytes. “TYSABRI binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leucocytes except neutrophils and inhibits the α4-mediated adhesion of leucocytes to their counter receptor(s)”. By assuming the pharmacotherapeutic role of the antagonist or competitive inhibitor of the vascular cell adhesion molecule-1 abbreviated to (VCAM-1) receptor, Natalizumab disables the action of the α4 integrin ligand, hence denying the transmigration through the endothelial cell tissue into the CNS. By actively blocking the ability of the VCAM- α4 receptor complex, Natalizumab interrupts the disease process as opposed to treating and mitigating symptoms consistent with other MS immunotherapy pharmaceuticals. Biogen, the commercial manufacturer of Tysabri in its Consumer Medicine Information states when Natalizumab is intravenously administered into the bloodstream along with other peptide antibodies, it is one of the most effective treatments for relapsing multiple sclerosis to date, given its efficacy and halting of the disease process and malignant leucocytes.

Despite natalizumab’s efficacy, MS is still untreatable to date as the lesions caused upon the myelin sheath is permanent due to MS’s degradation of oligodendrocytes and monitoring glial cells, as well as the lack of mitotic replication and repair of nerve cells, previous relapses or bouts of MS will have lasting effects. Natalizumab’s mechanism of action allows by preventing further malignant lymphocytic migration and hence diminishing further inflammation in the CNS, halting symptomology like lack of motor function and control. If natalizumab or similar immunotherapeutic pharmaceuticals are not administered, individuals and their families face MS’s chronic and painful effects of neurodegenerative and psychological symptoms, which strains life expectancy and overall life satisfaction

References

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