Case 6 - Extra Flashcards
what is the cellular composition of the nervous system
glia
neurones
what do glia do
insulate, support and nourish the neurones
what do the neurones do
sense change in environment, convey information and communicate these changes to other parts of the brain
what are the two major types of glial cells
microglia - CNS phagocytes
macroglia - scavenger cells that resemble macrophages and remove debris
what are the three types of macroglial cells
oligodendrocytes
Schwann cells
astrocytes
what are oligodendrocytes
myelin formation around axons in the CNS
what are Schwann cells
myelin formation around axons In the PNS
what are astrocytes
provide support for nerve fibres and maintain an appropriate neurotransmitter and chemical environment for neuronal signalling as well as maintaining the blood brain battier
features of oligodendrocytes
these are involved in myelin formation
these provide layers of membrane that insulate axons giving rise to a sheath
this sheath is interrupted at certain intervals
one oligodenodryte will provide myelin to several axons
myelin speeds up propagation of nerve impulses down the axons - saltatory conduction
what interrupts the sheath at certain intervals
Nodes of Ranvier
what are the features of Schwann cells
these are involved in myelin formation in PNS
one Schwann cells will provide myelin to a SINGLE axon
what are the two types of potentials
electronic potential and action potential
what is the electronic potential
this is a non prropagated local potential resulting from a local change in ionic conductance. when this spreads along a stretch of the neuronal membrane, it becomes exponentially smaller
neurones which are small in relation to their length, such as some in the brain only have this type of potential
which cells only have electronic potential
amacrine cells in retina
what is the action potential
this is a propagated impulse
longer neurones utilise electronic potentials to trigger the action potentials
initially there is always an electronic potential in a neurone - when this propagates it becomes an action potential
what is conduction
an active self propagating process, and the impulse moves along the nerve at a constant amplitude and velocity
what are the disruptions of ion channels in myelinated neurones
the initial segment and in sensory neurones, the first node of Ranvier are sites where impulses are normally generated, and other nodes of Ranvier are the sites to which the impulses jump during saltatory conduction
what is primary demyelination
myelin sheath is damaged or destroyed whilst axons remain intact
what is secondary demyelination
myelin sheath is damaged as a result of primary axonal damage
what does damage to the myelin sheath result in
impaired signal conduction
this results in a deficiency in sensation, movement, condition and other functions
what is the structure of the BBB
endothelial cells which line blood vessel walls of CNS
endothelial cells are connected by occludin and Claudin which forms tight junctions in order to create a barrier
to cross the BBB, molecules must be taken in by transport proteins / adhesion molecules or alterations in BBB permeability
how is the BBB compromised during inflammation
compromised to active recruitment of lymphocytes and monocytes and their migration across the barrier.
chemokine release allows activation of adhesion molecules on the lymphocytes and the monocytes resulting in interaction with endothelial cells of BBB which then activate the expression of MMP to degrade the barrier
what happens after disruptions the BBB
swelling and activation and infiltration of macrophages and lymphocytes that directly attack myelin sheaths within the CNS
what is the relapse part of the demyelination process
- T lymphocytes are involved: th1 and th17
Il-12 is responsible for the differentiation of naive Th cells into inflammatory T cells
over production of IL-12 is what causes the inflammation in MS patients, leading to too many inflammatory T cells
in MS, these lymphocytes cannot distinguish between normal and foreign myelin cells and thus attack the healthy myelin. this triggers further inflammation with activation of more cytokines and macrophages
what is the remission part of the demyelination process
oligodendrocytes cannot completely demyelinate or repair a destryoed myelin sheath
CNS thus recruits oligodendrocytes stem cells capable of proliferation and migration plus differentiation into mature myelinating oligodendrocytes
newly formed myelin are however thinner and not as effective
repeated attacks make this worse until a scar like plaque is built up around the damaged axons
inability of stem cells to myelinated properly can also be due to the astrocytes and prevailing inflammatory conditions
what is the pathogenesis initiated by
CD4+, th1 and th17 cells that react against self myelin antigenes and secrete cytokines
what do th1 cells secrete
IFN y which activates macrophages
what do th17 cells promote
the recruitment of leukocytes
what is the demyelination caused by
activated leukocytes and their injurious products.
they infiltrate in plaques and surrounding regions of the brain consist of T cells and macrophages
what is beta interferon
beta interferon is used for relapsing and remitting diseases
It is administered by a subcutaneous injection
This is defined as at least 2 attacks of neurological dysfunction over the previous 2/3 years followed by reasonable recovery
Interferon beta reduces relapse rates and prevents increase in lesions
what is the mechanism of action of beta interferon
- inhibiting T cell activation
- preventing T cell proliferation
- blocking T cell migration across the BBB
what is the galtiramer mode of action
binding to MHC Class 2 molecules preventing the binding of other antigens
Completing with myelin basic protein because it has a similar structure, for binding to T cell receptor
Myelin basic protein - protein believed to be important in the process of myelination of nerves in the nervous system by maintaining correct structure of myelin
inhibiting activation of MBP-reactive T cells shifts the population of T cells from pro-inflammatory Th1 cells to regulatory Th2 cells that suppress the inflammatory response
it is administered by subcutaneous injection
what are other names for glatiramer
glatiramer acetate
copaxane
copolymer
what is natilizumab / tysabri
alpha 4 intigrens are found on the surface of lymphocytes and monocytes and they are required for white blood cells to move into organ
Alpha 4 integrins interact with vascular cells adhesion molecule on vascular endothelial cells, to mediate adhesion and migration of immune cells across the BBB
Natalizumab is a monoclonal antibody which inhibits migration of leucocytes into the CNS
what is the mechanism of action of natalizumab
prevents binding of lymphocytes to vascular endothelium via alphabeta1 ligands sich as osteopontin and fibroectin which are involved in priming, activation and survival of leucocytes in CNS
it is useful in severe relapsing remitting MS that is unresponsive to other treatments
It is however, associated with a risk of progressive multifocal leukoencephalopathy and all patients need close monitoring for this and hypersensitivity reactions
what is another drug similar to natalizumab
alemtuzumab
it is an anti CD52 monoclonal antibody IV injection once yearly
it depletes t and B cells and modulates their activity with preservation of neutrophils and NK cells
reconstitution enriches for regulatory and memory T cells
however, adverse see effects include thyroid disorders
what are glucocorticoids
is a synthetic glucocorticoid drug
Used for its anti-inflammatory effects because glucocorticoids have a wide range of effects, including changes to metabolism and immune responses
Also inhibit the generation of some vasodilators
Dramatically reduce the manifestations of inflammation inhibiting both the early and late manifestations of inflammation. This is due to their profound effects on the concentration, distribution and function of peripheral leukocytes and to their suppressive effects on the inflammatory cytokines and chemokine and on other mediators of inflammation
glucocorticoids also inhibit the functions of tissue macrophages and other antigen presenting cells
Glucocorticoids influence the inflammatory response by reducing the prostaglandin, leukotriene and platelet activating factor synthesis that results from activation of phospholipase A2
Glucocorticoids reduce expression of COX-2 reducing the amount of enzyme available to produce prostaglandins
what is the mechanism of action of glucocorticoids
- block the arachidonic pathway
- enter cells
-bind to intracellular receptors in the cytoplasm - GR alpha and GR beta - receptor complex moves to nucleus
- alters gene transcription
- induction of lipocortin
- repression of IL3
