Neuroimmunology

Question 1

What cells are the immunecells of the CNS?

Answer 1

Microglia (macrophages of the CNS)

Question 2

Where does immunecells enter the CNS?

Answer 2

At perivascular space, choroid plexus and parenchyma
Both para- and transcellular route

Question 3

What are the entering of immunecells in CNS driven by?

Answer 3

Chemokines, primarily

Question 4

Are there any T-cells in healthy CNS?

Answer 4

Yes, memory T-cells

Question 5

What are some classical neuroinflammatory diseases?

Answer 5

Multiple sclerosis, myastenia gravis and infectious disease

Question 6

What are some other CNS diseases with an immune contribution?

Answer 6

Epilepsy, neurodegeneretive diseases, psychiatric disorders, cerebrovascular disorder

Question 7

What are some extraparenchymal macrophages in CNS?

Answer 7

• Meningeal macrophages: dural, lepto meningeal
• Perivascular macrophages
• Choroid plexus macrophages: stromal, kolmer

Question 8

What structure supplies the dura (in health) and CNS (in disease) with macrophages?

Answer 8

The skull bone marrow

Question 9

What role does microglia play in the prenatal developing brain?

Answer 9

• phagocytose neural progenitor cells (NPCs) in neurogenic zones
• express and release signaling factors
• phagocytose growing axons as part of the axonal growth regulation

Question 10

What role does microglia play in the postnatal developing brain?

Answer 10

• roles in the continued growth, and in refinement and function of the neural network and its myelination by, e.g., production of IGF-1
• phagocytosis of apoptotic NPCs

Question 11

Describe how microglia sculpture the brain during development.

Answer 11

• pruning of synapses decorated by complement proteins C1q and C3 (classical “eat me” signals)
• complement receptors expressed by microglia

Question 12

Describe the development and maintenance of microglia.

Answer 12

Depending on CSF1-R signaling - ligands: CSF1 produced by astrocytes, and IL-24 produced by neurons and likely glial cells

Question 13

What is “adult-onset leukoencephalopathy with axonal spheroids and pigmented glia” (ALSP), and what is it caused by?

Answer 13

A rare white matter disease leading to frontotemporal dementia and motor symptoms
Caused by mutations in the CSF1-R gene

Question 14

What are the TREM2/DAP12 genes involved in?

Answer 14

Phagocytosis by micorglia without inflammation

Question 15

What does mutations in TREM2/DAP12 lead to?

Answer 15

Phagocytic dysfunction of microglia in combination with inflammation

Question 16

Mention a disease caused by mutations in TREM2/DAP12.

Answer 16

Nasu-hakola disease, aka PLOSL

Question 17

Describe the micorglial homeostatic and immune surveillance functions.

Answer 17

• Dynamically scan the neuropil
• Contributes to synaptic scaling by release of tumor necrosis factor (TNF)
• Exposure of microglia to various immune stimuli (DAMP/PAMP) modulates microglial interaction with neurons
• Surveillance is activity dependent

Question 18

What are some age related changes in human microglia?

Answer 18

• reduced expression of many genes involved in actin dynamics
• changes in expression of genes involved in cell adhesion and axonal guidance
• changes in the expression of “sensome” genes

Question 19

Describe the microglial sensome.

Answer 19

Consists of genes that enable the microglia to “sense” dangerous stimuli as invading pathogens toxins and cellular debris

Question 20

Describe how the microglial phenotypes change throughout life.

Answer 20

The diversity are highest prenatally, lower postnatal, lowest in adulthood and then gets higher again in aging/pathology

Question 21

Describe the microglial response to injury.

Answer 21

• morphological changes/transformation aka activated microglia
• upregulated expression of “cellular markers”
• upregulated expression of MHC antigens essential for antigen presentation to T and B cells
• induction of proliferation (followed by apoptosis)
• upregulated expression of pathogen recognition receptors, scavenger receptors, cell adhesion molecules, cytokine-, chemokine- and complement receptors
• induction/increased production of cytokines, complement proteins and reactive oxygen species