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Me2ds0ci6 > Lecture 6 - 8 Types Of Cells In The CNS > Flashcards

Lecture 6 - 8 Types Of Cells In The CNS Flashcards

1
Q

List the cell types in the human CNS

A

Neurons
pericytes
neuroglia (microglia, astrocytes, oligodendrocytes)
endothelial cells
stem cells
Fibroblasts
leukocytes (T cells - scarce)

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2
Q

What are the cells that can only be found in the brain?

A

Oligodendrocytes and astrocytes

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3
Q

Give at least one neurological disease where these cells are majorly affected
-neurons
-astrocytes
-microglia
-endothelial cells
-oligodendrocytes

A

Neurons: Huntington’s disease, Parkinson’s disease, Alzheimer’s disease and many more

Astrocytes: astrocytomas, glioblastoma tumours, Neuromyelitis optics (NMO)

Microglia: Alzheimer’s

Endothelial cells: Alzheimer’s, Parkinson’s, stroke, infections, vascular diseases

Oligodendrocytes: multiple sclerosis, infections, anti-MOG disease

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4
Q

MICROGLIA
Role as immune cell

A
  • innate immune cells with monocytic origin
  • different function subsets exist -> express different immunological marks & have different shapes and locations
  • brain’s professional phagocytes. (Respond to a huge repertoire of cytokines to increase phagocytise activity during inflammation)
  • produce broad range of cytokines
  • present antigen but are not APCs
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5
Q

microglia
What does microglia do during brain injury

A

Communicates by secreting pro-inflammatory cytokines and present antigen to other immune cells.

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6
Q

Microglia
List some types of microglia

A

Perivascular, foamy, phagocytic, non-phagocytic, ramified, activated (inflammation), antigen presenting (disease)

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7
Q

Microglia true/false

A perivascular microglial cell can wrap around the back of a blood vessel.

Immunological microglial subset classification is accurate

There are many FDA therapies that specifically target microglia

A

true.

False. Immunological microglial subset classification is poor because neurological classification is mainly based on appearance (subjective) rather than function-related markers expression

False. There are not many approved microglial treatments because microglia are diverse in their function and their target elements are specific

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8
Q

What would be a better way of categorising microglial subsets

A

By immunological markers, cytokine production or chemo kind receptors which elude to cellular function but are depend highly on the disease.

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9
Q

Microglia
What are some potential therapeutic targets?

A
  1. Phagocytosis to clear debris as they are highly phagocytic
  2. Inflammatory through chemokine/cytokine strategies
  3. Reducing APC activity
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10
Q

Astrocytes
Major function in healthy CNS
“Progenitor qualities”

A
  • Support for neuronal cells
  • Maintenance/ support of neurovascular unit ()
  • Important source of neurotrophic factors (growth & survival)
  • Involved in neurotransmitter production and clearing excess transmitters from synapses.
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11
Q

Astrocytes

  1. are important for a few reasons
  2. What is important for functions stated
A
  1. Neuronal control and support
    If astrocytes lost - blood vessels die
    Blood -> neurovasculature -> astrocytes -> neurons
  2. The health of neurons
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12
Q

Astrocytes
During neuroinflammation
“Innate immune cells”

A
  • (innate) immunological functions but are not immune cells
  • actively migrate to injury/damage/inflammation site
  • produce & respond to cytokines/chemokines
  • chemokines - attract other immune cells to injury site
  • produce neurotrophic factors that aid in protecting neurons from cell death.
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13
Q

What are some common chemokines that brain cells produce to attract astrocytes and microglial cells?

A

MCP-1, IL-8, IP10, MIP1

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14
Q

What can be used to detect astrocytes
- stain
- cell features

A
  • nuclear stain (blue dots) and GFAP staining.
  • one of the few cell types that express GFAP.
    Huge cells. In tissue, wrap around other cells, forming a complex network around them.
    Produce very long processes -> allow communication with other cells
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15
Q

What happens if astrocytes are damaged

A

Production of neurotrophic factors

neurons will eventually die due to loss of neuronal support and vascular integrity.

Inflammatory mediators (by astrocytes) -> probably detrimental to neuronal cell health & maybe exacerbate damage.

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16
Q

List the parts of the neurovascular unit
(N = EPAP)

(Components of n unit)

A

Neurovascular unit = endothelial cells + pericytes + astrocytes + perivascular macrophages

Blood brain barrier,
Pericytes,
Endothelial cell with a tight junction,
Capillary,
ECM,
Astrocyte endfoot

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17
Q

Describe the arrangement of a neurovascular unit.
(Practice drawing the neurovascular unit)

A

An endothelial cell surrounds a capillary and is attach at both ends by a tight junction. A pericyte attaches onto the endothelial cell at one side. The pericyte, endothelial, capillary unit is surrounded by extra cellular matrix. Astrocyte endfoots cover the whole unit.

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18
Q

Blood brain barrier is

A

A layer of endothelial cells and its structures that separate the blood from the brain
About one cell thick.
A component of the neurovascular unit

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19
Q

Tight junctions

A

A family of proteins that seal the vessel forming a selective barrier between to solutes, cells and small molecules

Very high density between both endothelial cells.

20
Q

Molecules can only enter the brain through….

A

Junctional molecules or the cell body.

21
Q

What are the endothelial junctions

A

Tight junctions and adherens junctions

22
Q

What are the junctional molecules of the tight junctions

A

Occludin, Claudin, Zona-occludens, Cadherens, Junctional adhesion molecules (JAMs)

23
Q

Describe how the tight junctional molecules are related to each other.

A

Claudins and occluding are membrane bound molecules that link to zona occludens (ZO-1, ZO-2, ZO-3) which are scaffolding proteins. JAMs are located on the apical membrane and are held by ZO-1.

24
Q

Describe how adherens junctional molecules are related to each other

A

VE-cadherin and PECAM - membrane spanning proteins that can attach or detach depending on cytoplasmic proteins.

Cadherins - Important for formation of tight junctions

Catenins (beta, alpha, gamma) - hold the catenins in the cell cytoplasm.

25
Q

What happens to when there is a rise in intracellular calcium through the B2 receptor at the apical surface of the cell

A

The actin cytoskeleton is activated

26
Q

List the five ways that molecules can be transported into the endothelial cell of the blood brain barrier

A

Passive diffusion (Lipid, soluble non polar molecules)

ABC transporter efflux (lipid, soluble non polar molecules, conjugates)

Solute carriers [SLC] (glucose, AAs, small peptides, organic cations and anions)

Transcytosis [receptor mediated (RMT)/ Adsorptive mediated (AMT)] (leptin, insulin, IgG, lipoproteins, EGF, transferrin, histone)

Mononuclear cell migration

27
Q

Describe the mechanisms by which each transport method transports molecules

A
  1. Passive diffusion - passive diffusion
  2. ABC transport efflux - disrupt some molecules coming in passively and pump them out into the cytoplasm
  3. Solute carriers (SLC) - carrier mediated influx through active transport, bidirectional or unidirectional.
  4. RMT & AMT - through vesicles.
  5. Monocellular cell migration by immune cells or metastasis (melanoma) - modified tight junctions or diapedesis.
28
Q

ABC transported efflux and solute carriers (SLC)
- importance
- relation to therapies

A

-Important to supply brains of cells with important nutrients

-Challenging to create drug therapies - these transporters pump out molecules when they enter endothelial cell. The therapies cannot go pass endothelial cells into the brain.

29
Q

Working as an effective unit…

A

The vasculature coupled with glial networks and direct support neural networks are dependent on each other.

30
Q

What happens to immune cells such as T cells in the healthy CNS

A

A healthy amount of T cells will enter the brain at low frequency from the blood.

31
Q

Describe the role of immune cells in highly inflamed lesion of the brain (multiple sclerosis)

A

Around the lesion core - lots and lots of immune cells (T cells) surrounding the blood vessel and within lesions.

As they get further & further away - less immune cells (T cells)

32
Q

Why is it bad if there are a lot of T cells in the brain?

A

They are auto reactive against olligodendrocytes and can demyelinate them.

33
Q

Extravasion of leukocytes during neuroinflammation into the CNS. (Basolateral activation)

A
  1. Activation signals from the CNS through chemokines or cytokines release
  2. Leukocyte - endothelial interaction occurs
  3. Changes in endothelial cell when activated -> endothelial cell adhesion molecules attach to immune cell adhesion molecules
  4. Interaction between them -> weak attachment, (tethering/rolling)
  5. Strong adhesion
  6. Diapedesis -> immune cell goes through the BBB through cell/space between endothelial cell
34
Q

What leads to leukocyte migration into CNS during neuroinflammation

A

Infection, tissue injury, autoimmunity or drug mediated causes trigger activation signals from blood leading to apical activation.

35
Q

Define extravasation

A

Process of cells from blood through the endothelium barrier into injured/damaged/inflamed tissue by chemokines.

Leukocyte-endothelial interaction, rolling/tethering, strong adhesion, diapedesis

36
Q

Define trans-endothelial migration (TEM)

A

Movement of leukocytes from one side of the endothelial cell barrier to another directly through a cell in the barrier.

37
Q

Define paracellular migration

A

Migration of leukocytes into the CNS through the spaces in between adjacent endothelial cells by moving their junctional molecules

38
Q

Define diapedesis

A

When the cells squeeze through the junctions between adjacent endothelial cells to get to the inflamed tissue

39
Q

What is the role of endothelial adhesion molecules in leukocyte recruitment

A

Endothelial cell activated/inflamed/damaged -> upregulation of specific adhesion molecules by endothelium -> promotes strong interactions with leukocytes (T cells, B cells, monocytes)

Integrin adhesion molecules on endothelium help with catching/tethering leukocytes

40
Q

Match the Endothelial CAM to Leukocyte interacting CAM (these are integrins, CAMs and CDs - immune cells )

E selectin
P selectin

ICAM-1 CD99
VCAM-1 CD31

A

E-selectin - CD162 & CD15
P-selectin - CD162 & CD24

ICAM-1 - CD11a, CD11b, CD11c
VCAM-1 - Integrins CD49d, CD29(VLA4)

CD99 - CD99
CD31 - CD31

41
Q

E-selectin, P-selectin, VCAM-1, ICAM-1 have heteromeric interaction while CD99 & CD31 have homomeric interaction because……

A

E-selectin, P-selectin, VCAM-1, ICAM-1 interact with other molecules while CD99 & CD31 interacts with itself.

42
Q

Three scenarios that fall under neuroinflammation, example and disease damage

A
  1. Autoimmune disease (AID)/ Multiple sclerosis (MS) / immune system targets and destroys myelin sheath
  2. Viral infection / viral/bacterial encephalitis
  3. Cancer / gliomas/GBM / fatal forms of cancer
43
Q

Therapies/ solutions to treat these types of neurological disease

A
  1. AID - block leukocyte entry across NVU, reduce neuroinflammation
  2. Viral infection - anti viral responses need, neuroinflammation beneficial
  3. Cancer - remove tumour without damage, right type of neuroinflammation promoted without causing damage
44
Q

How to prevent neuroinflammation and potential therapy strategy

A

Reduce immune cell coming from vasculature, reduce immune cells into brain.

Disrupt molecular leukocyte-endothelial interactions through antibodies that bind to adhesion molecules on endothelial cell -> two molecules cannot interact -> reduce lesion number and B&T cell number. Less chemokines -> less recruitment

45
Q

What happens when there is a massive amount of immune cells

A

CD8 T cells -> damage anything -> remove tethering potential of immune cells

Me2ds0ci6 (28 decks)

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