Case 6 - Extra

Question 1

what is the cellular composition of the nervous system

Answer 1

glia
neurones

Question 2

what do glia do

Answer 2

insulate, support and nourish the neurones

Question 3

what do the neurones do

Answer 3

sense change in environment, convey information and communicate these changes to other parts of the brain

Question 4

what are the two major types of glial cells

Answer 4

microglia - CNS phagocytes
macroglia - scavenger cells that resemble macrophages and remove debris

Question 5

what are the three types of macroglial cells

Answer 5

oligodendrocytes
Schwann cells
astrocytes

Question 6

what are oligodendrocytes

Answer 6

myelin formation around axons in the CNS

Question 7

what are Schwann cells

Answer 7

myelin formation around axons In the PNS

Question 8

what are astrocytes

Answer 8

provide support for nerve fibres and maintain an appropriate neurotransmitter and chemical environment for neuronal signalling as well as maintaining the blood brain battier

Question 9

features of oligodendrocytes

Answer 9

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

Question 10

what interrupts the sheath at certain intervals

Answer 10

Nodes of Ranvier

Question 11

what are the features of Schwann cells

Answer 11

these are involved in myelin formation in PNS
one Schwann cells will provide myelin to a SINGLE axon

Question 12

what are the two types of potentials

Answer 12

electronic potential and action potential

Question 13

what is the electronic potential

Answer 13

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

Question 14

which cells only have electronic potential

Answer 14

amacrine cells in retina

Question 15

what is the action potential

Answer 15

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

Question 16

what is conduction

Answer 16

an active self propagating process, and the impulse moves along the nerve at a constant amplitude and velocity

Question 17

what are the disruptions of ion channels in myelinated neurones

Answer 17

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

Question 18

what is primary demyelination

Answer 18

myelin sheath is damaged or destroyed whilst axons remain intact

Question 19

what is secondary demyelination

Answer 19

myelin sheath is damaged as a result of primary axonal damage

Question 20

what does damage to the myelin sheath result in

Answer 20

impaired signal conduction

this results in a deficiency in sensation, movement, condition and other functions

Question 21

what is the structure of the BBB

Answer 21

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

Question 22

how is the BBB compromised during inflammation

Answer 22

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

Question 23

what happens after disruptions the BBB

Answer 23

swelling and activation and infiltration of macrophages and lymphocytes that directly attack myelin sheaths within the CNS

Question 24

what is the relapse part of the demyelination process

Answer 24

• 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

Question 25

what is the remission part of the demyelination process

Answer 25

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

Question 26

what is the pathogenesis initiated by

Answer 26

CD4+, th1 and th17 cells that react against self myelin antigenes and secrete cytokines

Question 27

what do th1 cells secrete

Answer 27

IFN y which activates macrophages

Question 28

what do th17 cells promote

Answer 28

the recruitment of leukocytes

Question 29

what is the demyelination caused by

Answer 29

activated leukocytes and their injurious products.
they infiltrate in plaques and surrounding regions of the brain consist of T cells and macrophages

Question 30

what is beta interferon

Answer 30

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

Question 31

what is the mechanism of action of beta interferon

Answer 31

• inhibiting T cell activation
• preventing T cell proliferation
• blocking T cell migration across the BBB

Question 32

what is the galtiramer mode of action

Answer 32

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

Question 33

what are other names for glatiramer

Answer 33

glatiramer acetate
copaxane
copolymer

Question 34

what is natilizumab / tysabri

Answer 34

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

Question 35

what is the mechanism of action of natalizumab

Answer 35

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

Question 36

what is another drug similar to natalizumab

Answer 36

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

Question 37

what are glucocorticoids

Answer 37

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

Question 38

what is the mechanism of action of glucocorticoids

Answer 38

• 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