Multiple Sclerosis is aninflammatory demyelinating disease of Central Nervous System with a complexpathology that varies with respect to the extent and character of inflammation,demyelination, gliosis, axonal injury and remyelinating 3. It is referredto as a bi-phasic disease with inflammatory phase that leads to a subsequent neurodegenerativephase late. The first step in diagnosis of MS is non-invasive and relativelyeasy, Magnetic Resonance Imaging (MRI). MRI examination relies on evidences of blood-brainbarrier leakage which is defined by the presence of gadolinium-DTPA leakage 4.
However, this may not differentiate active MS plaques from inactive MS plaques.Classification system developed on the basis of lesions are as acute, chronicand active 8. Other lesion classifications include Botrapp andLucchinetti system which determines the time of on-set and progression of thedisease. It further divides into active (active, early and active, late), mixedactive/inactive and inactive types 10. Multiple sclerosis isa T cell mediated disease. T cells reactive to myelin basic protein (MBP) getsactive by molecular mimicry i.e myelin basic protein shares similarities withpathogens such as influenza virus, herpes virus, papilloma virus, Epstein-Barrvirus and Pseudomonas in terms ofhaving contact critical residues.
Residue 84-101 of MBP share a stretch of fourto six amino acids with these pathogens which are capable of binding to MHC andT cells. Activation of myelin reactive T cells also take place by Superantigens14. Activated lymphocytes extravasate to penetrate non-fenestratedCNS by the virtue of ?4-integrin and very late antigen-4 (VLA-4).
These furtherpasses through ECM by degrading it with matrix metalloproteases, gelatinase Aand gelatinase B thus getting accessed to white matter surrounding axons 14.Several therapies involving blockage of VLA-4 can be designed. Tissue inhibitorof matrix metalloproteases (TIMP-1) which is induced by cytokines (TNF?) andHydroxamic acid reverses MS by inhibiting demyelination and maintaining theintegrity of blood-brain barrier 14. Once the activated lymphocyteis inside the brain, it mounts targeted immune response such as complementactivation, activation of T cells, cytokines production, activation ofmacrophages.
T and B cells are sensitized by antigens released from CNS. Dendriticcells present neural antigens thus strongly stimulate T cell response. Sensitizedimmune cells undergo clonal expansion and infiltrate the CNS. B cells recounterneural antigens, mature to plasma cells and release large amounts of Ig-?autoantibodies. Clonally expanded Tc cells encounter their specificpeptide ligand presented by microglial cells in association with MHC I whichfurther directs damage of the expressing cells. TH cells migrateinto the CNS and encounter antigens that are presented by microglial cells onMHC II which results into heightened production of inflammatory cytokines (TNF?).These cytokines attract macrophages which direct phagocytic attack on the myelinsheath.
This impairs saltatory conduction along the axon and producespathophysiologic effect