Lecture 26: Foundations of Neuroinflammation

Question 1

What is the immune system?

Answer 1

our body’s defence system which consists innate and adaptive immunity

Question 2

What is innate immunity?

Answer 2

non-specific, from birth

Question 3

What is adaptive immunity?

Answer 3

acquired, specific

Question 4

What are the different type of barriers which prevent pathogen exposure?

Answer 4

physical e.g. skin, mucosae, mucus
mechanical e.g. flushing mechanisms such as cilia, fluid flow
chemical e.g. enzymes and antibodies, pH

Question 5

What is the first line of defence in innate immunity?

Answer 5

skin and hair = physical barriers
gastric secretions, tears, perspiration, lysozyme = chemical barriers
bodily functions to expel microbes/foreign particles = mechanical barriers

Question 6

What is the second line of defence in innate immunity?

Answer 6

interferons, complement, iron binding proteins and antimicrobial proteins as well as NK cells and macrophages

Question 7

What is the role of NK cells?

Answer 7

non-specific

release perforin to cause cytolysis in target cells

Question 8

What is the role of macrophages?

Answer 8

phagocytosis

APCs which keep foreign fragments on cells surface

Question 9

What are the different subtypes of macrophages?

Answer 9

histiocytes (skin)
Kupffer cells (liver)
osteoclasts (bone)
microglia (brain)

Question 10

What is the role of adaptive immunity?

Answer 10

defence against specific invaders such as bacteria, toxins and viruses and occurs after antigen exposure

Question 11

How does adaptive immunity differ from innate immunity?

Answer 11

specificity and memory

Question 12

Where do many lymphocytes reside within the brain?

Answer 12

in the meninges and choroid plexus and only few lymphocytes are found in the brain parenchyma (dorsal hippocampus and olfactory nucleus)

Question 13

What are the most dominant immune cells in the brain?

Answer 13

resident microglia which comprise 80% of brain immune cells

Question 14

What are the different types of immune cells in the brain?

Answer 14

myeloid cells, monocytes / macrophages, dendritic cells, T-cells, B-cells and NK cells

Question 15

What are the functional barriers of the brain?

Answer 15

blood-brain barrier, blood-CSF barrier and pia-arachnoid

another present only in early brain development between the CSF and brain interstitial fluid

Question 16

Where is the blood-brain barrier located?

Answer 16

at the level of the cerebral endothelial cells

Question 17

Where is the blood-CSF barrier located?

Answer 17

at the epithelial cells of the choroid plexuses with the 4 cerebral ventricles

Question 18

What are the cells of the neuro ependyma / neuroepithelium linked by (during early brain development)?

Answer 18

strap junctions which limits intercellular diffusion of large molecules

Question 19

What is the BBB composed of?

Answer 19

capillary endothelial cells and surrounding perivascular elements (basal lamina, pericyte, astrocyte end-foot and interneurons)

Question 20

What are tight junctions in the BBB established by?

Answer 20

the interaction between the transmembrane proteins (claudins, occludins, and junctional adhesion molecules) on adjacent endothelial cells

Question 21

What is the c-terminal of these transmembrane proteins linked to? What may the presence of PKC result in?

Answer 21

the cytoskeletal actin through ZO-1 (zona occludin-1)
may increase phosphorylation of ZO-1 and disrupt association of ZO-1 and the actin cytoskeleton – causing disruption of the BBB

Question 22

How is the structure of central capillaries different to peripheral capillaries?

Answer 22

absence of fenestrations and more extensive tight junctions

Question 23

How is the function of central capillaries different to peripheral capillaries?

Answer 23

impermeable to most substances, sparse pinocytic vesicular transport, increased expression of transport and carrier proteins, limited paracellular and transcellular transport

Question 24

What are microglia?

Answer 24

a specialised population of macrophage-like cells found in the CNS

Question 25

What are microglia considered as?

Answer 25

immune sentinels capable of coordinating a potent inflammatory response

Question 26

What is the role of microglia?

Answer 26

phagocytosis of apoptotic cells and debris, myelin turnover, synaptic organisation, control of neuronal excitability, brain protection and repair

Question 27

What are astrocytes?

Answer 27

a population of cells with distinct morphological and functional characteristics that differ within brain areas

Question 28

What do astrocytes have regulatory roles in?

Answer 28

neurogenesis, synaptogenesis, controlling BBB permeability and maintaining cellular homeostasis also can induce and facilitate progression of the inflammatory state

Question 29

What does loss of astrocytic function lead to?

Answer 29

cell senescence and neurodegenerative disorders

Question 30

What is complement?

Answer 30

collection of proteins (plasma and cellular) ~40 | controlled by regulatory proteins

Question 31

What are the different pathways of complement?

Answer 31

inflammation -> stimulate histamine phagocytosis and opsonisation MAC (cell lysis)

Question 32

What is the role of classical complement proteins?

Answer 32

mediate microglial phagocytosis of synapses during CNS development and disease

Question 33

What does CNS injury and infection lead to?

Answer 33

increased complement protein expression

Question 34

How can CNS inflammation occur?

Answer 34

does not require invasion by circulating cells but can occur as a result of local tissue response to changes in the local environment

Question 35

How beneficial is the neuroinflammatory response to degenerative diseases?

Answer 35

the initial neuroinflammatory response is beneficial, but long-term, chronic overproduction of cytokines is detrimental and is thought to ’fuel’ the degenerative process

Question 36

What is the role of cytokines?

Answer 36

allow cells to communicate with one another to orchestrate complex processes involving many different cell types

Question 37

What is a key function of cytokines?

Answer 37

their functional redundancy and pleiotropism i.e. a large number of cells respond to cytokines

Question 38

What are interleukins?

Answer 38

the first cytokines to be studied and are the original or prototypic inflammatory cytokine

Question 39

What is TNF-alpha?

Answer 39

a member of the TNF superfamily of ligands, many promoting inflammation

Question 40

What are the important functions of TNF-alpha in the brain?

Answer 40

microglia and astrocyte activation, regulation of BBB permeability, febrile responses, glutamatergic transmission and synaptic plasticity

Question 41

What is TGF-beta?

Answer 41

transforming growth factor - beta are a superfamily of cytokines with over 50 members

Question 42

What is the role of TGF-beta?

Answer 42

able to transform cell lines and induce anchorage-independent growth regulation of neuroinflammation and apoptosis in traumatic brain injury

Question 43

What is the main function of chemokines?

Answer 43

to stimulate chemotaxis of macrophages, neurotrophils and other lymphocytes to sites of injury, damage or infection regulate leukocyte infiltration across the BBB

Question 44

What is the inflammatory response dictated by?

Answer 44

a balance of pro-inflammatory and anti-inflammatory factors | chronic inflammation is thought to occur when this fine balance is somehow perturbed

Question 45

Which cytokines are thought to be proinflammatory?

Answer 45

TNF-a, IL-17 and IL-1b

Question 46

What happens in high enough concentrations of immunogenic factors within the brain?

Answer 46

activation of microglia which causes them to undergo morphological and chemical changes including the production and release of cytokines and reactive oxygen species (ROS)

Question 47

How are astrocytes activated?

Answer 47

the up-regulation of glial fibrillary acidic protein (GFAP) in response to most types of CNS injury widely used as a marker of astrocyte reactivity

Question 48

What does NF-kB control and what is NF-kB signalling triggered by?

Answer 48

controls many aspects of astrocyte pro-inflammatory responses triggered by cytokines released by microglia (and other cells in the CNS)

Question 49

Why is bi-directional communication between astrocytes important?

Answer 49

regulates their responses to neuroinflammation

Question 50

What do activated astrocytes release and why?

Answer 50

Glu, NO and TNF to drive apoptosis in oligodendrocytes | cytokines for communication

Question 51

What do interactions between activated astrocytes and endothelial cells increase?

Answer 51

BBB permeability and this facilitates leukocyte infiltration

Question 52

What can astrocytes recruit perivascular spaces and CNS parenchyma?

Answer 52

leukocytes through secretion of a certain number of factors

Question 53

What can BBB disruption be caused by?

Answer 53

a number of insults (stroke) or an increase in inflammatory cytokines

Question 54

What does glia activation cause?

Answer 54

the release of pro-inflammatory cytokines which breakdown the BBB -> this leads to the infiltration of inflammatory cells, mainly neutrophils

Question 55

What do activated neutrophils release?

Answer 55

pro-inflammatory cytokines which cause further glia activation leading to neuronal injury

Question 56

What does ischemic stroke result from?

Answer 56

permanent or transient occlusion of a major brain artery or one of its branches

Question 57

What happens to microglia in the hours and days following a stroke?

Answer 57

they become ameboid and take on an M1 phenotype

Question 58

What is a feature that is common to Alzheimer's and Parkinson's disease and frontotemporal dementia?

Answer 58

microglia activation