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NEUR30002 > Lecture 26: Foundations of Neuroinflammation > Flashcards

Lecture 26: Foundations of Neuroinflammation Flashcards

1
Q

What is the immune system?

A

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

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2
Q

What is innate immunity?

A

non-specific, from birth

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3
Q

What is adaptive immunity?

A

acquired, specific

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4
Q

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

A

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

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5
Q

What is the first line of defence in innate immunity?

A

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

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6
Q

What is the second line of defence in innate immunity?

A

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

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7
Q

What is the role of NK cells?

A

non-specific

release perforin to cause cytolysis in target cells

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8
Q

What is the role of macrophages?

A

phagocytosis

APCs which keep foreign fragments on cells surface

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9
Q

What are the different subtypes of macrophages?

A

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

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10
Q

What is the role of adaptive immunity?

A

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

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11
Q

How does adaptive immunity differ from innate immunity?

A

specificity and memory

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12
Q

Where do many lymphocytes reside within the brain?

A

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

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13
Q

What are the most dominant immune cells in the brain?

A

resident microglia which comprise 80% of brain immune cells

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14
Q

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

A

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

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15
Q

What are the functional barriers of the brain?

A

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

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

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16
Q

Where is the blood-brain barrier located?

A

at the level of the cerebral endothelial cells

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17
Q

Where is the blood-CSF barrier located?

A

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

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18
Q

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

A

strap junctions which limits intercellular diffusion of large molecules

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19
Q

What is the BBB composed of?

A

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

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20
Q

What are tight junctions in the BBB established by?

A

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

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21
Q

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

A

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

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22
Q

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

A

absence of fenestrations and more extensive tight junctions

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23
Q

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

A

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

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24
Q

What are microglia?

A

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

25
Q

What are microglia considered as?

A

immune sentinels capable of coordinating a potent inflammatory response

26
Q

What is the role of microglia?

A

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

27
Q

What are astrocytes?

A

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

28
Q

What do astrocytes have regulatory roles in?

A

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

29
Q

What does loss of astrocytic function lead to?

A

cell senescence and neurodegenerative disorders

30
Q

What is complement?

A

collection of proteins (plasma and cellular) ~40

controlled by regulatory proteins

31
Q

What are the different pathways of complement?

A

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

32
Q

What is the role of classical complement proteins?

A

mediate microglial phagocytosis of synapses during CNS development and disease

33
Q

What does CNS injury and infection lead to?

A

increased complement protein expression

34
Q

How can CNS inflammation occur?

A

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

35
Q

How beneficial is the neuroinflammatory response to degenerative diseases?

A

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

36
Q

What is the role of cytokines?

A

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

37
Q

What is a key function of cytokines?

A

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

38
Q

What are interleukins?

A

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

39
Q

What is TNF-alpha?

A

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

40
Q

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

A

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

41
Q

What is TGF-beta?

A

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

42
Q

What is the role of TGF-beta?

A

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

43
Q

What is the main function of chemokines?

A

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

44
Q

What is the inflammatory response dictated by?

A

a balance of pro-inflammatory and anti-inflammatory factors

chronic inflammation is thought to occur when this fine balance is somehow perturbed

45
Q

Which cytokines are thought to be proinflammatory?

A

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

46
Q

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

A

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

47
Q

How are astrocytes activated?

A

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

48
Q

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

A

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

49
Q

Why is bi-directional communication between astrocytes important?

A

regulates their responses to neuroinflammation

50
Q

What do activated astrocytes release and why?

A

Glu, NO and TNF to drive apoptosis in oligodendrocytes

cytokines for communication

51
Q

What do interactions between activated astrocytes and endothelial cells increase?

A

BBB permeability and this facilitates leukocyte infiltration

52
Q

What can astrocytes recruit perivascular spaces and CNS parenchyma?

A

leukocytes through secretion of a certain number of factors

53
Q

What can BBB disruption be caused by?

A

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

54
Q

What does glia activation cause?

A

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

55
Q

What do activated neutrophils release?

A

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

56
Q

What does ischemic stroke result from?

A

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

57
Q

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

A

they become ameboid and take on an M1 phenotype

58
Q

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

A

microglia activation

NEUR30002 (36 decks)

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