Organ-specific immunity: BRAIN Flashcards
This deck contains the lectures" "Inflammation of the CNS", "Immune privilege; blood-brain barrier", and "Innate and adaptive immune responses in the brain"
How many T lymphocytes patrol the CSF or perivascular space for pathogens in healthy individuals?
150 000
How do memory CD4 T cells return to the blood stream?
Via lymphatic vessels in the meningeal spaces and the deep cervical lymph nodes
Which parts of the brain play a role in the neuro-immune system?
- CSF
- Blood-CSF barrier
- Dural lymphatic vessels
What are the types of inflammation that can occur in the brain? (3)
- Bacterial
- Viral
- Parasitic
Name examples of bacterial agents involved in neonate brain inflammation (4)
- E.coli
- Listeria
- Staphylococci
- Pneumococci
Name examples of bacterial agents involved in adult brain inflammation (4)
- Pneumococci
- Meningococci
- N. meningitidis
- Staphylococci
- H. influenzae
What is meningitis?
Inflammation of the meninges
Why do you die from meningitis?
Swelling due to adema
What is cerebritis?
Inflammation of brain tissue (“encephalitis”)
What causes brain abscesses? (3)
- Endocarditis
- Lung infections
- Abdominal infections
What is a severe complication of meningococcus meningitis?
Waterhouse-Friedrichsen syndrome (sepsis)
What are specific inflammations affecting the CNS? (4)
- Tuberculosis
- Sarcoidosis
- Neuro-lues (Syphilis stage 3)
- Lyme disease
What happens when tabes dorsalis occurs during syphilis?
Demyelination of sensory neurons afferent to the spinal cord
Name three examples of viral inflammation in the brain
- Herpes simplex type 1
- Rabies
- Poliomyelitis
What are the five viral entry routes into the brain?
- Via PNS
- Via bloodvessel
- Via olfactory epithelium
- Via microglia
- Infection of BMVECs
In which group of patients are parasitic brain inflammations prevalent?
Immunodeficient patients (transplantation; AIDS)
What are the two types of vasculitis?
- Systemic
- Primary granulomatous
Name three demyelinating diseases
- Multiple sclerosis
- Acute demyelinating encephalomyelitis (ADEM)
- Progressive myelo-encephalopathy (PML)
What is the role of macrophages during MS?
Destroying myelin sheets
What is a MS plaque?
Spot of demyelination
What is the CNS?
Everything inside the skull and spine, but also the optic nerve
What is the definition of immune privilege?
The permissiveness and proneness of a tissue or anatomical site to develop and sustain immune activity
What are immune privileged sites?
- Brain
- Eyes
- Placenta + fetus
- Testicles
Why are the placenta and fetus immune privileged sites?
If not, you would generate an immune response against your own child
What are the three main questions when considering immune privilege?
- Tolerance of the CNS for foreign bodies
- Migration of antigens within the CNS to SLOs
- Migration of lymphocytes
What are the mechanisms by which tumors avoid immune recognition? (5)
- Low immunogenicity
- Tumor treated as self-antigen
- Antigenic modulation
- Tumor-induced immune suppression
- Tumor induced privileged site
How does a tumor induce a privileged site?
By secreting factors creating a physical barrier to the immune system
Which structure secludes the CNS?
Blood-brain barrier
What is the blood-brain barrier?
Unique composition of specialized endothelial cells and ascessory cells
Name unique features of the endothelial cells of the blood-brain barrier (3)
- Very tight junctions between the endothelial cells –> prevents spontaneous passing of large cells or molecules
- Active pumps (pump in- AND out of the CNS)
- Large amounts of pericytes
What do pericytes secrete? (2)
- Pro- and anti-inflammatory mediators
- Growth factors
Where do you end up if you pass the endothelial layer of the bb-barrier? What is this structure?
Perivascular space. Small fluid-filled structures that surround blood vessels in the brain
What is the most immunogenic site of the CNS?
Perivascular space
Why are the dual sinuses the ideal spot to be if you want immune surveillance in your brain?
This is the spot where blood and waste (molecules/potential antigens) are ultimately drained from your brain
Why is it convenient to have mesenchymal structure in the PVS?
They form a framework for resident and surveilling leukocytes to be maintained and stored, waiting for antigens to appear.
What is the natural habitat of CNS T-cells? What do they express to regulate immune responses in the brain?
Perivascular space. Express inhibitory factors
What is an extra control step for lymphocytes in the brain?
Reactivation in PVS –> Mandatory step to enter the brain parenchyma
What are the differences/similarities between perivascular macrophages and microglia? (4)
- Phagocyte active (both)
- Activated by IFN-y vs requires multiple cytokines for activation
- Specialized vs moderate APC
- Many vs. few co-stimulatory molecules
Why does the brain parenchyma not inflame or elicit immune responses? (2)
- The innate immune cells/microglia are much less able to elicit inflammation vs. perivascular macrophages
- Extremely high expression of anti-inflammatory mediators in the brain parenchyma
Example of an anti-inflammatory molecule expressed in the brain parenchyma
CD200
Summary: what are the reasons why your brain does not get inflamed easily? (3)
- Very controlled entry of cells
- Compartmentalized, immunogenic region in CNS
- Parenchyma is loaded with anti-inflammatory mediators
What are the routes a T cell can take to enter the PVS? (2)
- Meningal vasculature
- Choroid plexus
Which cells appear at the site of initial antigenic challenge and stay there for the remainder of the life of a mouse?
Resident memory T cells
What is the function of CD69?
Functional agonist of all kinds of molecules that promote tissue egress
How does the inflamed endothelium control diapedesis of activated immune cells? (4)
- Tethering/Adhere to endothelial wall
- Rolling
- Activation
- Arrest
- Diapedesis
In which direction do leukocytes role across the endothelium?
Rolling into opposite direction of the blood flow
Which lymph nodes are involved in CNS drainage? (mouse)
- Superficial cervicals
- Deep cervicals
- Lumbar
Summary: What factors contribute to the CNS being an immune privileged site? (5)
- Limited capacity of parenchymal APCs
- Anti-inflammatory signals in the CNS parenchyma
- Strictly compartimentalized CNS lymphocyte presence
- Seclusion of CNS behind a blood brain barrier
- Requirement of T cell re-activation after crossing the BBB
What are the major cell types of the CNS? (3)
- Neurons
- Macroglia - astrocytes/oligodendrocytes
- Microglia
