Organ-specific immunity: BRAIN

Question 1

How many T lymphocytes patrol the CSF or perivascular space for pathogens in healthy individuals?

Answer 1

150 000

Question 2

How do memory CD4 T cells return to the blood stream?

Answer 2

Via lymphatic vessels in the meningeal spaces and the deep cervical lymph nodes

Question 3

Which parts of the brain play a role in the neuro-immune system?

Answer 3

• CSF
• Blood-CSF barrier
• Dural lymphatic vessels

Question 4

What are the types of inflammation that can occur in the brain? (3)

Answer 4

• Bacterial
• Viral
• Parasitic

Question 5

Name examples of bacterial agents involved in neonate brain inflammation (4)

Answer 5

• E.coli
• Listeria
• Staphylococci
• Pneumococci

Question 6

Name examples of bacterial agents involved in adult brain inflammation (4)

Answer 6

• Pneumococci
• Meningococci
• N. meningitidis
• Staphylococci
• H. influenzae

Question 7

What is meningitis?

Answer 7

Inflammation of the meninges

Question 8

Why do you die from meningitis?

Answer 8

Swelling due to adema

Question 9

What is cerebritis?

Answer 9

Inflammation of brain tissue (“encephalitis”)

Question 10

What causes brain abscesses? (3)

Answer 10

• Endocarditis
• Lung infections
• Abdominal infections

Question 11

What is a severe complication of meningococcus meningitis?

Answer 11

Waterhouse-Friedrichsen syndrome (sepsis)

Question 12

What are specific inflammations affecting the CNS? (4)

Answer 12

• Tuberculosis
• Sarcoidosis
• Neuro-lues (Syphilis stage 3)
• Lyme disease

Question 13

What happens when tabes dorsalis occurs during syphilis?

Answer 13

Demyelination of sensory neurons afferent to the spinal cord

Question 14

Name three examples of viral inflammation in the brain

Answer 14

• Herpes simplex type 1
• Rabies
• Poliomyelitis

Question 15

What are the five viral entry routes into the brain?

Answer 15

• Via PNS
• Via bloodvessel
• Via olfactory epithelium
• Via microglia
• Infection of BMVECs

Question 16

In which group of patients are parasitic brain inflammations prevalent?

Answer 16

Immunodeficient patients (transplantation; AIDS)

Question 17

What are the two types of vasculitis?

Answer 17

• Systemic
• Primary granulomatous

Question 18

Name three demyelinating diseases

Answer 18

• Multiple sclerosis
• Acute demyelinating encephalomyelitis (ADEM)
• Progressive myelo-encephalopathy (PML)

Question 19

What is the role of macrophages during MS?

Answer 19

Destroying myelin sheets

Question 20

What is a MS plaque?

Answer 20

Spot of demyelination

Question 21

What is the CNS?

Answer 21

Everything inside the skull and spine, but also the optic nerve

Question 22

What is the definition of immune privilege?

Answer 22

The permissiveness and proneness of a tissue or anatomical site to develop and sustain immune activity

Question 23

What are immune privileged sites?

Answer 23

• Brain
• Eyes
• Placenta + fetus
• Testicles

Question 24

Why are the placenta and fetus immune privileged sites?

Answer 24

If not, you would generate an immune response against your own child

Question 25

What are the three main questions when considering immune privilege?

Answer 25

- Tolerance of the CNS for foreign bodies - Migration of antigens within the CNS to SLOs - Migration of lymphocytes

Question 26

What are the mechanisms by which tumors avoid immune recognition? (5)

Answer 26

- Low immunogenicity - Tumor treated as self-antigen - Antigenic modulation - Tumor-induced immune suppression - Tumor induced privileged site

Question 27

How does a tumor induce a privileged site?

Answer 27

By secreting factors creating a physical barrier to the immune system

Question 28

Which structure secludes the CNS?

Answer 28

Blood-brain barrier

Question 29

What is the blood-brain barrier?

Answer 29

Unique composition of specialized endothelial cells and ascessory cells

Question 30

Name unique features of the endothelial cells of the blood-brain barrier (3)

Answer 30

- 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

Question 31

What do pericytes secrete? (2)

Answer 31

- Pro- and anti-inflammatory mediators - Growth factors

Question 32

Where do you end up if you pass the endothelial layer of the bb-barrier? What is this structure?

Answer 32

Perivascular space. Small fluid-filled structures that surround blood vessels in the brain

Question 33

What is the most immunogenic site of the CNS?

Answer 33

Perivascular space

Question 34

Why are the dual sinuses the ideal spot to be if you want immune surveillance in your brain?

Answer 34

This is the spot where blood and waste (molecules/potential antigens) are ultimately drained from your brain

Question 35

Why is it convenient to have mesenchymal structure in the PVS?

Answer 35

They form a framework for resident and surveilling leukocytes to be maintained and stored, waiting for antigens to appear.

Question 36

What is the natural habitat of CNS T-cells? What do they express to regulate immune responses in the brain?

Answer 36

Perivascular space. Express inhibitory factors

Question 37

What is an extra control step for lymphocytes in the brain?

Answer 37

Reactivation in PVS --> Mandatory step to enter the brain parenchyma

Question 38

What are the differences/similarities between perivascular macrophages and microglia? (4)

Answer 38

- Phagocyte active (both) - Activated by IFN-y vs requires multiple cytokines for activation - Specialized vs moderate APC - Many vs. few co-stimulatory molecules

Question 39

Why does the brain parenchyma not inflame or elicit immune responses? (2)

Answer 39

- 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

Question 40

Example of an anti-inflammatory molecule expressed in the brain parenchyma

Answer 40

CD200

Question 41

Summary: what are the reasons why your brain does not get inflamed easily? (3)

Answer 41

- Very controlled entry of cells - Compartmentalized, immunogenic region in CNS - Parenchyma is loaded with anti-inflammatory mediators

Question 42

What are the routes a T cell can take to enter the PVS? (2)

Answer 42

- Meningal vasculature - Choroid plexus

Question 43

Which cells appear at the site of initial antigenic challenge and stay there for the remainder of the life of a mouse?

Answer 43

Resident memory T cells

Question 44

What is the function of CD69?

Answer 44

Functional agonist of all kinds of molecules that promote tissue egress

Question 45

How does the inflamed endothelium control diapedesis of activated immune cells? (4)

Answer 45

- Tethering/Adhere to endothelial wall - Rolling - Activation - Arrest - Diapedesis

Question 46

In which direction do leukocytes role across the endothelium?

Answer 46

Rolling into opposite direction of the blood flow

Question 47

Which lymph nodes are involved in CNS drainage? (mouse)

Answer 47

- Superficial cervicals - Deep cervicals - Lumbar

Question 48

Summary: What factors contribute to the CNS being an immune privileged site? (5)

Answer 48

- 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

Question 49

What are the major cell types of the CNS? (3)

Answer 49

- Neurons - Macroglia - astrocytes/oligodendrocytes - Microglia