CNS Immune Response

Question 1

why do you not want to have a strong innate response in the CNS

Answer 1

innate response causes significant inflammation and damage to tissues

do not want in the CNS because:
1. CNS has poor regenerative ability - can not replace or repair damaged neurons
2. skull makes inflammatory response and increase in tissue volume dangerous

Question 2

is access to brain parenchyma, meninges, or CSF restricted or free

Answer 2

very restricted

Question 3

how does CNS immune surveillance differ from peripheral immune function

Answer 3

• low level of MHC expression during health
• does NOT contain APCs within parenchyma; only located at the blood/brain interface

Question 4

what are the 3 sites that immune cells can use to access the CNS

Answer 4

1. BBB
2. BCSFB
3. meningeal barrier

Question 5

blood brain barrier

Answer 5

MOST RESTRICTIVE BARRIER

endothelial tight junctions + glia limitans that protects the brain parenchyma

immune cells must cross TWO layers to reach brain:
1. cross endothelial tight junctions into perivascular space
2. cross glia limitans though tight junctions between astrocyte end feet into brain parenchyma

Question 6

blood CSF barrier

Answer 6

fenestrated capillaries + choroid epithelial cells connected with tight junctions that protects the CSF

allows ANTIGEN EXPERIENCED CD4 T CELLS to enter for immune surveillance

only requires one layer to enter CSF because capillaries are fenestrated
- moves across fenestrated capillaries into choroid plexus then across choroid plexus epithelial tight junctions into subarachnoid space (site of CSF)

Question 7

meningeal barrier

Answer 7

FIRST BARRIER crossed by immune cells
- first sign of infection reaching CNS is meningitis

perivascular space where meningeal vessels branch into subarachnoid space
(dura + pia + arachnoid mater)

capillaries only have ONE layer to pass through (no inner and outer membrane)

Question 8

are most immune responses initiated in the CNS

Answer 8

NO - initiated in periphery first because that’s where majority of pathogens enter into before spreading into CNS

Question 9

what are the primary guardians of the CNS

Answer 9

• microglia
• circulating immune cells

Question 10

microglia

Answer 10

brain resident immune cells that act as the primary watchmen of the brain parenchyma
- maintain synapses and adult CNS turnover
- “clean up” during sleep
- support neurons

Question 11

function of microglia

Answer 11

circulate in extracellular space and sample every few hours - activated by antigen in CNS

Question 12

characteristics of resting microglia

Answer 12

• low MHC II expression
• maintained in resting state by receptor - ligand interactions with neurons
• endogenous growth factors decrease MHC and co-stimulatory molecule expression to remain quiescent

Question 13

characteristics of activated microglia

Answer 13

• high MHC II expresion
• high co-stimulatory molecule expression (B7 or CD80/40)
• look like DCs/macrophages
• able to activate T cells
• release cytokines and chemokine to recruit peripheral immune cells to the brain via chemokine gradient

Question 14

what branch of immune system to microglia activate

Answer 14

adaptive immune system

Question 15

astrocytes

Answer 15

secrete TGF-B and IL-10 to prevent over activation of microglia

downregulates the pro-inflammatory immune response

Question 16

what kind of immune cells patrol the normal CSF

Answer 16

CD4+ memory T cells

normal CSF should have low cellularity - only a few mononuclear cells

Question 17

function of mast cells in CNS immunity

Answer 17

reside in the brain, spinal cord, and meninges

produce TNF-a and IL1B (vasoactive substances) to increase vessel permeability and initiate the inflammatory response

regulates BBB function and T cell migration to CNS

Question 18

what are the ways that pathogens can enter the CNS

Answer 18

1. infect endothelial cells
2. enter via BBB (requires release of vasoactive substances)
3. intra-leukocyte transport
4. retrograde axonal transport (avoids immune detection)

Question 19

how does transient viremia spread to CNS

Answer 19

blood borne viruses can induce TNFa release to increase vessel leakiness –> greater chance of spreading to CNS

higher viremia induce greater trigger signals that increase likelihood of reaching CNS

Question 20

how do infected neurons signal for immune help

Answer 20

virally infected neurons produce T cell chemoattractant (CXCL10)

T cells locate the infected cell by binding to CXCR3 receptor on infected cell surface
- if infected cell does not display CXCR3 –> T cell can’t locate it –> decrease immune response –> increased mortality

Question 21

what part of the immune system protects against viral replication before reaching the CNS

Answer 21

• general immune response
• antibodies

Question 22

what part of the immune system protects against neuroinvasion once the virus has already replicated/caused inflammation

Answer 22

specific T cell responses

Question 23

what must CNS immune response include to be protective

Answer 23

antibody production and NON lytic effector cells

Question 24

where are antibodies for CNS protection produced

Answer 24

in the CSF

CNS must contain antibody secreting cells and antigen specific CD8 T cells

Question 25

normal CSF protein levels

Answer 25

low protein (measured in mg/dL instead of g/dL like plasma)

Question 26

what does high protein CSF indicate

Answer 26

inflammation –> stimulates local globulins
- neoplasia or necrosis

non-inflammatory –> stimulates albumin

Question 27

normal CNS cellularity

Answer 27

low - 0-2 cells/ul

Question 28

what does CSF cytology during bacterial infection look like

Answer 28

pleocytosis w/ neutrophil dominance

Question 29

what does CSF cytology during fungal/protozoal/parasitic infection look like

Answer 29

pleocytosis w/ neutrophils, macrophages, lymphocytes, and eosinophils

Question 30

what does CSF cytology during viral infection look like

Answer 30

mononuclear pleocytosis (lymphocytes)