Multiple late antigen-4 (VLA-4). These further passes through ECM

Multiple Sclerosis is an
inflammatory demyelinating disease of Central Nervous System with a complex
pathology that varies with respect to the extent and character of inflammation,
demyelination, gliosis, axonal injury and remyelinating 3. It is referred
to as a bi-phasic disease with inflammatory phase that leads to a subsequent neurodegenerative
phase late. The first step in diagnosis of MS is non-invasive and relatively
easy, Magnetic Resonance Imaging (MRI). MRI examination relies on evidences of blood-brain
barrier 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, chronic
and active 8. Other lesion classifications include Botrapp and
Lucchinetti system which determines the time of on-set and progression of the
disease. It further divides into active (active, early and active, late), mixed
active/inactive and inactive types 10.

 

Multiple sclerosis is
a T cell mediated disease. T cells reactive to myelin basic protein (MBP) gets
active by molecular mimicry i.e myelin basic protein shares similarities with
pathogens such as influenza virus, herpes virus, papilloma virus, Epstein-Barr
virus and Pseudomonas in terms of
having contact critical residues. Residue 84-101 of MBP share a stretch of four
to six amino acids with these pathogens which are capable of binding to MHC and
T cells. Activation of myelin reactive T cells also take place by Superantigens
14. Activated lymphocytes extravasate to penetrate non-fenestrated
CNS by the virtue of ?4-integrin and very late antigen-4 (VLA-4). These further
passes through ECM by degrading it with matrix metalloproteases, gelatinase A
and gelatinase B thus getting accessed to white matter surrounding axons 14.
Several therapies involving blockage of VLA-4 can be designed. Tissue inhibitor
of matrix metalloproteases (TIMP-1) which is induced by cytokines (TNF?) and
Hydroxamic acid reverses MS by inhibiting demyelination and maintaining the
integrity of blood-brain barrier 14. Once the activated lymphocyte
is inside the brain, it mounts targeted immune response such as complement
activation, activation of T cells, cytokines production, activation of
macrophages. T and B cells are sensitized by antigens released from CNS. Dendritic
cells present neural antigens thus strongly stimulate T cell response. Sensitized
immune cells undergo clonal expansion and infiltrate the CNS. B cells recounter
neural antigens, mature to plasma cells and release large amounts of Ig-?
autoantibodies. Clonally expanded Tc cells encounter their specific
peptide ligand presented by microglial cells in association with MHC I which
further directs damage of the expressing cells. TH cells migrate
into the CNS and encounter antigens that are presented by microglial cells on
MHC II which results into heightened production of inflammatory cytokines (TNF?).
These cytokines attract macrophages which direct phagocytic attack on the myelin
sheath. This impairs saltatory conduction along the axon and produces
pathophysiologic effect

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