Foundation - The immune-privileged organ: a neuroimmunology primer. Flashcards
Innate Immune System
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
Adaptive Immune System
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
Humoral
a type of adaptive immune response
not a cell (antibodies)
vs Cellular (a cell) (cytotoxic lymphocytes)
afferent and the efferent arms of the immune system
Afferent - gathering of info - APCs
Efferent - effect of that action (activated lymphocytes, macrophages)
Immune response = your body response
to antigens (does not need to be infectious ex. dust)
- Sneezing, cough, inflammation, etc.
Inflammation =
movement of immune cells into an area
- Field of battle – need to be balanced (two extremes possible - bad)
Splinter/Cut and immune response
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
The damage-response framework
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
Immune privlaged orgons
eyes
placenta (important to not attack foreign fetus)
[brain - importnat - no space for swelling]
Immune responses have to be controlled in the CNS
because no space for swelling
rigid layers cover the CNS
IP (immune privilege) can be a double-edge sword because
- Prevent complete clearance of pathogens (- latency)
- Provide protection to tumors
Evidence for CNS immune-privilege
- Tissues implanted on brain parenchyma are not rejected (if immune would reject)
- Bacterial/viral antigens injected on brain parenchyma failed to evoke an adaptive response (microglia - do have response)
- At steady-state, very low levels of lymphocytes seen on perivascular spaces (none in the parenchyma)
(everywhere else - lymphocytes always in and out) - Absence of lymphatic vessels
(key role in immunity) - Presence of BBB
(immune cannot cross)
Evidence against immune-privilege in CNS
- Tissues are rejected if transplanted into ventricles (or SAS)
- PAMPs on CSF-filled compartments elicit a rapid infiltration of immune cells (inflammation – meningitis)
- Large numbers of phagocytes (antigen presenting cells) are constantly present on CSF-filled compartments (and the parenchyma has microglia!)
- Discovery of meningeal lymphatic vessels (works with glympatics similar role to lympatics everywhere)
- Lymphocytes can be forced to cross BBB (artificial situation, but biologically possible!)
Each CNS barrier establish compartments with different relationships with the immune system
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)
Neuroimmune system – the meninges
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
The part of brain with the fastest and largest immune response
the meninges (Neuroimmune system)
-Exhibit rapid inflammatory responses
Neuroimmune system – the ventricles
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]
Neuroimmune system – the brain parenchyma
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
Steps after virus gain access to parenchyma
Regulatory T cells (aka Tregs) are
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)
Two classes of Tregs
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
Disregulated immune response
- Own proteins cause microglia activation – autoimmune disease
- Cytokines released
- Incoming lymphocytes are activated against that same antigen
- Activated APCs go to lymph node ® activate more lymphocytes
- More lymphocytes are recruited
- Constant presence of antigen inhibits anti-inflammatory response
- BBB collapses (because chronic)- more infiltration
- Neurodegeneration ensues (neurons get killed)
No Treggs b/c signaling continues - is no switch to healing
