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Neuro > Neuroinflammation > Flashcards

Neuroinflammation Flashcards

1
Q

Which cells are the resident immune cells of the brain?

A

Microglia

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2
Q

What does it mean for the brain to be immune privileged?

A

Microglia are the first line of defence

The BBB significantly limits the entry of immune cells (T cells) in to the brain under normal conditions

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3
Q

What are microglia and astrocytes activated by?

A

Damaged cells (DAMPS)

Macromolecules (PAMPS)

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4
Q

What can prolonged activation of astrocytes and microglia lead to?

A

The production of damaging molecules that contribute to the pathogenesis of several neurological disorder

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5
Q

Name some diseases in which prolonged activation of microglia and astrocytes is implicated in

A

Alzheimers and Parkinsons

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6
Q

Name the three components of the immune system in the brain

A
  1. Microglia
  2. T cells, B Cells and macrophages can infiltrate the CNS from periphery
  3. Astrocytes, while not immune cells, play an auxiliary role in immune response
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7
Q

Under normal conditions how many T and B cells are in the brain?

A

Very few are present as the brain is immune privileged

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8
Q

Which cells have innate immune receptors also found in T cells, macrophages etc ?

A

Microglia, Astrocytes, Neurons, and Endothelial cells

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9
Q

Give an example of a PAMP in the CNS

A

Microbial/viral proteins

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10
Q

Give an example of DAMPS in the CNS

A

Misfolded and aggregated proteins - beta amyloid- in Alzheimers and alpha-synuclein in Parkinsons

Extracellular nucleic acid (RNA/DNA) - dead neurons are engulfed away (like in the SN in Parkinson’s)

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11
Q

Give examples of when neuroinflammation is okay

A

Short term activation is fine

  • Recruitment of T and B cells to remove infection
  • Clearance of dead neurons during developmental pruning
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12
Q

When is neuroinflammation bad?

A

Prolonged neuroinflammation has been implicated in development and progression of neurological disorders such as Alzheimer’s and Parkinson’s.

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13
Q

Describe the activation of microglia

A

Binding of PAMPS and DAMPS activate microglia –> Change morphology and become mobile.

Depending on activation signals, become M1 or M2-like

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14
Q

What are Astrocytes activated by?

A

DAMPS, PAMPS, cytokines and chemokines

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15
Q

What do neurotrophic factors do?

A

They send a message to the neurons to keep living

Pro-survival signals

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16
Q

Which brain cells act as APCs?

A

Microglia

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17
Q

Compare M1 and M2 microglia

A

M1s:
↓ neurotrophic factors
↑ pro-inflammatory cytokines

Make free radicals
and they lead to:
•Chronic brain inflammation
•Damage to neurons
•Neuronal dysfunction

M2:
↑ phagocytosis
↑ neurotrophic factors

Antigen presentation
can be switched off easily

Make anti-inflammatory cytokine 
and they lead to:
•Clearance of debris
•Resolution of inflammation
•Limited or no damage to neurons
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18
Q

Activation of microglia can produce signalling molecules that affect which other cells of the CNS?

A

Astrocytes, neurones, BBB

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19
Q

Which signalling molecules are released by activated microglia?

A

Cytokines, Chemokines, NO and ROS

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20
Q

What do cytokines do in neuroinflammation?

A

Activate further microglia and astrocytes

Induce apoptosis and necrosis of neurons, astrocytes, microglia

21
Q

Name some cytokines involved in neuroinflammation

A

IL-1β, IL-6, IFN-g, TNF-a (Can activate apoptosis)

22
Q

What is the role of chemokine in the brain?

A

Promote BBB permeability (letting T cells in eg.)

Cause dysfunction and apoptosis/necrosis of astrocytes, microglia and neurons

23
Q

What effect do NO and ROS have in the brain?

A

Damage DNA, proteins, lipids

Induce apoptosis/necrosis of astrocytes, microglia and neurons

24
Q

How does an unreactive astrocyte compare in morphology to a reactive one?

A

The astrocyte leaflet is thicker

25
Q

What are the 2 types of reactive astrocytes?

A

Hypertrophic ansd scar-forming

26
Q

Compare the functions of hypertrophic anf scar forming astrocytes

A

Hypertrophic: Affect function of neighbouring cells via cytokines, chemokines, NO, neurotrophic factors

Are similar to microglia

Scar-forming:
Permanent rearrangement of brain architecture

Are activated in case of serious brain trauma

27
Q

Compare hypertrophic vs scar-forming astrocytes in their behaviour

A

Hypertrophic don’t proliferate, scar-forming do

Hypertrophic don’t migrate, scar-forming do

Hypertrophic have individual territory, scar forming don’t

Hypertrophic are reversible if stimuli is removed, scar-forming are permanent

Hypertrophic interact with neurons, oligodendrocytes, BBB and scar-forming interact with non-neuronal inflammatory cells

28
Q

Give examples of the actions of hypertrophic and scar-forming astrocytes

A

Hypertrophic: reactive astrocytes at BBB change shape and release chemokines increasing permeability of BBB to T cells

Scar-forming: form physical border around inflamed or damaged tissue thus segregating area from neighbouring functional neuronal circuits

29
Q

What are the two steps for T/B cells and macrophages to enter the BBB?

A

Crossing the endothelial cell lining and breaching the glial limitans

30
Q

Describe the process of T cells crossing the endothelial cell lining

A

T cells breach endothelial lining and remain in perivascular space where they have access to antigen presenting cells

T cells undergoing immunosurveillance can drain away via CSF

If they present to antigen, T cells undergo transendothelial migration

31
Q

What is trans endothelial migration?

A

Entry of T cells and other immune cells strictly regulated by the BBB

32
Q

Give examples of some molecules involved in trans endothelial migration

A

Endothelial cells (Selectins, ICAM-1)

T cells (Integrins)

33
Q

Describe the steps of trans endothelial migration?

A
  1. Capture/Rolling: T cell integrin binds to VCAM-1 on the endothelium, T cell PSGL-1 binds to P-selectin on the endothelium
  2. Chemokines can bind to T cells to activate them
  3. Arrest: ICAM-1 Binds to T cell integrins
  4. Crawling: ICAM-2 binds
  5. Diapedesis - paracellular or transcellular (there is debate as to which is correct)
34
Q

Describe the process of breaching the glial limitans

A

Presentation of antigens and/or expression of pro-inflammatory molecules such as chemokines and cytokines allows entry of T cells into the CNS

Cross glial limitans because cytokines make astrocyte feet and pericytes relax and allow the BBB to open

35
Q

What is the glial limitans?

A

It is a wall of protein

36
Q

Describe MS demographics

A

~ 1/1000 in UK

Affects women more than men

37
Q

What is MS?

A

Autoimmune diseases

Immune cells attack myelinated neurons

38
Q

What are the pathological hallmarks of MS?

A

Inflammation,
Demyelination, Remyelination, Neurodegeneration and Glial scar formation

-Usually inflammation happens and then stops and repeats (heals)

39
Q

What happens every time the BBB opens?

A

It gets damaged a bit

40
Q

What are focal plaques?

A

Places in MS where demyelination occurs

41
Q

How does demyelination have an affect in MS?

A

Demyelinating disease disrupts conduction of action potentials along neurons.

42
Q

What causes MS?

A

Unknown

43
Q

Describe the role of inflammatory cells in MS

A

T cells and microglia: At active lesions initial response is from T cells and activated microglia.

Myelin damage correlates with T cell and activated microglia number

T/B cells and macrophages: Once myelin gets destroyed, secondary recruitment of T cells, B cells and macrophages leads to profound damage to BBB

44
Q

What effect does MS have on myelination?

A

Loss of oligodendrocyte processes and oligodendrocyte apoptosis

Myelin highly susceptible to damage from cytokines and reactive oxygen species

45
Q

Why does relapsing and remitting MS turn into progressive?

A

Due to increasing damage to the BBB

46
Q

Which diseases are reactiveastrocytes and microglia found in?

A

Alzheimer’s and Parkinson’s disease

47
Q

Is neuroinflammation a cause or consequence of disease?

A

Might be because of varients in microglia

Or could be reacting to the already existing dead neurons

48
Q

Why does beta-amyloid activate microglia?

A

It mimics bacterial cell walls

49
Q

What is the most likely role of neuroinflammation in disease progression?

A

Prolonged activation and release of mediators such as cytokines and ROS/NO

Neuro (23 decks)

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