Foundation - The immune-privileged organ: a neuroimmunology primer.

Question 1

Innate Immune System

Answer 1

Immediate, 1st and 2nd lines of defense

Physical (and chemical) barriers; phagocytes (macrophages, etc.)

Nonspecific, against all invaders

Act equally against any forgen “thing”
fast, always ready

Question 2

Adaptive Immune System

Answer 2

Reinforcements, last line of defense (>48 hr to 1-2 weeks) - 10-14 days with vaccine to kick in

Humoral (not a cell) (antibodies) and Cellular (a cell) (cytotoxic lymphocytes)

Specific against each antigen, provides memory (immunity)

very specific, takes time

Question 3

Humoral

Answer 3

a type of adaptive immune response

not a cell (antibodies)
vs Cellular (a cell) (cytotoxic lymphocytes)

Question 4

afferent and the efferent arms of the immune system

Answer 4

Afferent - gathering of info - APCs
Efferent - effect of that action (activated lymphocytes, macrophages)

Question 5

Immune response = your body response

Answer 5

to antigens (does not need to be infectious ex. dust)
- Sneezing, cough, inflammation, etc.

Question 6

Inflammation =

Answer 6

movement of immune cells into an area
- Field of battle – need to be balanced (two extremes possible - bad)

Question 7

Splinter/Cut and immune response

Answer 7

skin barrier damaged

DAMPs - piece of own cells - supposed to be inside [piece of mitochondria comes out (OJ from bacteria)]

PAMPs - Bacteria

Innate cells - recognize PAMPs and DAMPs

Chemokines - blood - inc LAM and JAMs

Influx of Cells - swelling
Capliaties expand

Killing of pathogens

Immune cells need to switch to healars (if not happen - collateral damage)

Healing tissue

Question 8

The damage-response framework

Answer 8

Outcome depends on host response

• moves along the parabola
• Host and pathogen factors can affect parabola

If weak vs strong immune system and host damage/benefit - changes outcome

Question 9

Immune privlaged orgons

Answer 9

eyes
placenta (important to not attack foreign fetus)
[brain - importnat - no space for swelling]

Question 10

Immune responses have to be controlled in the CNS

Answer 10

because no space for swelling
rigid layers cover the CNS

Question 11

IP (immune privilege) can be a double-edge sword because

Answer 11

• Prevent complete clearance of pathogens (- latency)
• Provide protection to tumors

Question 12

Evidence for CNS immune-privilege

Answer 12

1. Tissues implanted on brain parenchyma are not rejected (if immune would reject)
2. Bacterial/viral antigens injected on brain parenchyma failed to evoke an adaptive response (microglia - do have response)
3. At steady-state, very low levels of lymphocytes seen on perivascular spaces (none in the parenchyma)
   (everywhere else - lymphocytes always in and out)
4. Absence of lymphatic vessels
   (key role in immunity)
5. Presence of BBB
   (immune cannot cross)

Question 13

Evidence against immune-privilege in CNS

Answer 13

1. Tissues are rejected if transplanted into ventricles (or SAS)
2. PAMPs on CSF-filled compartments elicit a rapid infiltration of immune cells (inflammation – meningitis)
3. Large numbers of phagocytes (antigen presenting cells) are constantly present on CSF-filled compartments (and the parenchyma has microglia!)
4. Discovery of meningeal lymphatic vessels (works with glympatics similar role to lympatics everywhere)
5. Lymphocytes can be forced to cross BBB (artificial situation, but biologically possible!)

Question 14

Each CNS barrier establish compartments with different relationships with the immune system

Answer 14

Meninges – incoming and outgoing connections through vasculature and lymphatics (also SLYM)

Ventricles – incoming and outgoing connections through choroid plexus (feinistrated vessels - easy immune move)

Parenchyma – no connection, only resident cells (microglia) (rely on glympatics - has limitstions - cannot go in through lympatics - some antigents not soluble in H20)

Question 15

Neuroimmune system – the meninges

Answer 15

Bathed by both CNS fluids: CSF and ISF

Exhibit rapid inflammatory responses [part of brain with fastest and largest immune response]

Activated T cells can enter SAS from arachnoid or dural veins

SLYM and lymphatic vessels - constantly sample - hve immune response

Question 16

The part of brain with the fastest and largest immune response

Answer 16

the meninges (Neuroimmune system)

-Exhibit rapid inflammatory responses

Question 17

Neuroimmune system – the ventricles

Answer 17

Choroid plexi generates CSF

Contains fenestrated vessels:
- Easy access for immune cells to choroid plexus stromal space

Large number of resident APCs

Sample CSF (and ISF that drains there)

Upon activation, T cells can cross into ventricles

Exhibit rapid inflammatory responses

fenestrated capilary - fiaciltate crossing of immune [far from lympatics vs menengies]

Question 18

Neuroimmune system – the brain parenchyma

Answer 18

Protected by BBB, no direct entry

ISF washes parenchyma and drains into veins and SAS (limited to small, soluble antigens)

No direct access to lymph nodes

Microglia do not leave the CNS

No lymphocytes at steady-state

Low numbers of APCs in perivascular spaces flanking the BBB

Cut-off from adaptive immune system - importance of glymphatics

Question 19

Steps after virus gain access to parenchyma

Answer 19

Question 20

Regulatory T cells (aka Tregs) are

Answer 20

are lymphocytes

Suppress and regulate the function of other immune cells

• There are no T cells in the brain, so these are adaptive Tregs
• After resolution, they undergo apoptosis (b/c not normally in the brain)

Question 21

Two classes of Tregs

Answer 21

Natural – created in the thymus - go into every orgon in the body (not brain)

Adaptive – formed by differentiation in the affected tissue - ones in the brain

Question 22

Disregulated immune response

Answer 22

1. Own proteins cause microglia activation – autoimmune disease
2. Cytokines released
3. Incoming lymphocytes are activated against that same antigen
4. Activated APCs go to lymph node ® activate more lymphocytes
5. More lymphocytes are recruited
6. Constant presence of antigen inhibits anti-inflammatory response
7. BBB collapses (because chronic)- more infiltration
8. Neurodegeneration ensues (neurons get killed)

No Treggs b/c signaling continues - is no switch to healing