Neuroimmunology Flashcards
What cells are the immunecells of the CNS?
Microglia (macrophages of the CNS)
Where does immunecells enter the CNS?
At perivascular space, choroid plexus and parenchyma
Both para- and transcellular route
What are the entering of immunecells in CNS driven by?
Chemokines, primarily
Are there any T-cells in healthy CNS?
Yes, memory T-cells
What are some classical neuroinflammatory diseases?
Multiple sclerosis, myastenia gravis and infectious disease
What are some other CNS diseases with an immune contribution?
Epilepsy, neurodegeneretive diseases, psychiatric disorders, cerebrovascular disorder
What are some extraparenchymal macrophages in CNS?
- Meningeal macrophages: dural, lepto meningeal
- Perivascular macrophages
- Choroid plexus macrophages: stromal, kolmer
What structure supplies the dura (in health) and CNS (in disease) with macrophages?
The skull bone marrow
What role does microglia play in the prenatal developing brain?
- phagocytose neural progenitor cells (NPCs) in neurogenic zones
- express and release signaling factors
- phagocytose growing axons as part of the axonal growth regulation
What role does microglia play in the postnatal developing brain?
- 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
Describe how microglia sculpture the brain during development.
- pruning of synapses decorated by complement proteins C1q and C3 (classical “eat me” signals)
- complement receptors expressed by microglia
Describe the development and maintenance of microglia.
Depending on CSF1-R signaling - ligands: CSF1 produced by astrocytes, and IL-24 produced by neurons and likely glial cells
What is “adult-onset leukoencephalopathy with axonal spheroids and pigmented glia” (ALSP), and what is it caused by?
A rare white matter disease leading to frontotemporal dementia and motor symptoms
Caused by mutations in the CSF1-R gene
What are the TREM2/DAP12 genes involved in?
Phagocytosis by micorglia without inflammation
What does mutations in TREM2/DAP12 lead to?
Phagocytic dysfunction of microglia in combination with inflammation
Mention a disease caused by mutations in TREM2/DAP12.
Nasu-hakola disease, aka PLOSL
Describe the micorglial homeostatic and immune surveillance functions.
- 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
What are some age related changes in human microglia?
- 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
Describe the microglial sensome.
Consists of genes that enable the microglia to “sense” dangerous stimuli as invading pathogens toxins and cellular debris
Describe how the microglial phenotypes change throughout life.
The diversity are highest prenatally, lower postnatal, lowest in adulthood and then gets higher again in aging/pathology
Describe the microglial response to injury.
- 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
