Lecture 26: Foundations of Neuroinflammation Flashcards
What is the immune system?
our body’s defence system which consists innate and adaptive immunity
What is innate immunity?
non-specific, from birth
What is adaptive immunity?
acquired, specific
What are the different type of barriers which prevent pathogen exposure?
physical e.g. skin, mucosae, mucus
mechanical e.g. flushing mechanisms such as cilia, fluid flow
chemical e.g. enzymes and antibodies, pH
What is the first line of defence in innate immunity?
skin and hair = physical barriers
gastric secretions, tears, perspiration, lysozyme = chemical barriers
bodily functions to expel microbes/foreign particles = mechanical barriers
What is the second line of defence in innate immunity?
interferons, complement, iron binding proteins and antimicrobial proteins as well as NK cells and macrophages
What is the role of NK cells?
non-specific
release perforin to cause cytolysis in target cells
What is the role of macrophages?
phagocytosis
APCs which keep foreign fragments on cells surface
What are the different subtypes of macrophages?
histiocytes (skin)
Kupffer cells (liver)
osteoclasts (bone)
microglia (brain)
What is the role of adaptive immunity?
defence against specific invaders such as bacteria, toxins and viruses and occurs after antigen exposure
How does adaptive immunity differ from innate immunity?
specificity and memory
Where do many lymphocytes reside within the brain?
in the meninges and choroid plexus and only few lymphocytes are found in the brain parenchyma (dorsal hippocampus and olfactory nucleus)
What are the most dominant immune cells in the brain?
resident microglia which comprise 80% of brain immune cells
What are the different types of immune cells in the brain?
myeloid cells, monocytes / macrophages, dendritic cells, T-cells, B-cells and NK cells
What are the functional barriers of the brain?
blood-brain barrier, blood-CSF barrier and pia-arachnoid
another present only in early brain development between the CSF and brain interstitial fluid
Where is the blood-brain barrier located?
at the level of the cerebral endothelial cells
Where is the blood-CSF barrier located?
at the epithelial cells of the choroid plexuses with the 4 cerebral ventricles
What are the cells of the neuro ependyma / neuroepithelium linked by (during early brain development)?
strap junctions which limits intercellular diffusion of large molecules
What is the BBB composed of?
capillary endothelial cells and surrounding perivascular elements (basal lamina, pericyte, astrocyte end-foot and interneurons)
What are tight junctions in the BBB established by?
the interaction between the transmembrane proteins (claudins, occludins, and junctional adhesion molecules) on adjacent endothelial cells
What is the c-terminal of these transmembrane proteins linked to? What may the presence of PKC result in?
the cytoskeletal actin through ZO-1 (zona occludin-1)
may increase phosphorylation of ZO-1 and disrupt association of ZO-1 and the actin cytoskeleton – causing disruption of the BBB
How is the structure of central capillaries different to peripheral capillaries?
absence of fenestrations and more extensive tight junctions
How is the function of central capillaries different to peripheral capillaries?
impermeable to most substances, sparse pinocytic vesicular transport, increased expression of transport and carrier proteins, limited paracellular and transcellular transport
What are microglia?
a specialised population of macrophage-like cells found in the CNS
What are microglia considered as?
immune sentinels capable of coordinating a potent inflammatory response
What is the role of microglia?
phagocytosis of apoptotic cells and debris, myelin turnover, synaptic organisation, control of neuronal excitability, brain protection and repair
What are astrocytes?
a population of cells with distinct morphological and functional characteristics that differ within brain areas
What do astrocytes have regulatory roles in?
neurogenesis, synaptogenesis, controlling BBB permeability and maintaining cellular homeostasis
also can induce and facilitate progression of the inflammatory state
What does loss of astrocytic function lead to?
cell senescence and neurodegenerative disorders
What is complement?
collection of proteins (plasma and cellular) ~40
controlled by regulatory proteins
What are the different pathways of complement?
inflammation -> stimulate histamine
phagocytosis and opsonisation
MAC (cell lysis)
What is the role of classical complement proteins?
mediate microglial phagocytosis of synapses during CNS development and disease
What does CNS injury and infection lead to?
increased complement protein expression
How can CNS inflammation occur?
does not require invasion by circulating cells but can occur as a result of local tissue response to changes in the local environment
How beneficial is the neuroinflammatory response to degenerative diseases?
the initial neuroinflammatory response is beneficial, but long-term, chronic overproduction of cytokines is detrimental and is thought to ’fuel’ the degenerative process
What is the role of cytokines?
allow cells to communicate with one another to orchestrate complex processes involving many different cell types
What is a key function of cytokines?
their functional redundancy and pleiotropism i.e. a large number of cells respond to cytokines
What are interleukins?
the first cytokines to be studied and are the original or prototypic inflammatory cytokine
What is TNF-alpha?
a member of the TNF superfamily of ligands, many promoting inflammation
What are the important functions of TNF-alpha in the brain?
microglia and astrocyte activation, regulation of BBB permeability, febrile responses, glutamatergic transmission and synaptic plasticity
What is TGF-beta?
transforming growth factor - beta are a superfamily of cytokines with over 50 members
What is the role of TGF-beta?
able to transform cell lines and induce anchorage-independent growth
regulation of neuroinflammation and apoptosis in traumatic brain injury
What is the main function of chemokines?
to stimulate chemotaxis of macrophages, neurotrophils and other lymphocytes to sites of injury, damage or infection
regulate leukocyte infiltration across the BBB
What is the inflammatory response dictated by?
a balance of pro-inflammatory and anti-inflammatory factors
chronic inflammation is thought to occur when this fine balance is somehow perturbed
Which cytokines are thought to be proinflammatory?
TNF-a, IL-17 and IL-1b
What happens in high enough concentrations of immunogenic factors within the brain?
activation of microglia which causes them to undergo morphological and chemical changes including the production and release of cytokines and reactive oxygen species (ROS)
How are astrocytes activated?
the up-regulation of glial fibrillary acidic protein (GFAP) in response to most types of CNS injury
widely used as a marker of astrocyte reactivity
What does NF-kB control and what is NF-kB signalling triggered by?
controls many aspects of astrocyte pro-inflammatory responses
triggered by cytokines released by microglia (and other cells in the CNS)
Why is bi-directional communication between astrocytes important?
regulates their responses to neuroinflammation
What do activated astrocytes release and why?
Glu, NO and TNF to drive apoptosis in oligodendrocytes
cytokines for communication
What do interactions between activated astrocytes and endothelial cells increase?
BBB permeability and this facilitates leukocyte infiltration
What can astrocytes recruit perivascular spaces and CNS parenchyma?
leukocytes through secretion of a certain number of factors
What can BBB disruption be caused by?
a number of insults (stroke) or an increase in inflammatory cytokines
What does glia activation cause?
the release of pro-inflammatory cytokines which breakdown the BBB -> this leads to the infiltration of inflammatory cells, mainly neutrophils
What do activated neutrophils release?
pro-inflammatory cytokines which cause further glia activation leading to neuronal injury
What does ischemic stroke result from?
permanent or transient occlusion of a major brain artery or one of its branches
What happens to microglia in the hours and days following a stroke?
they become ameboid and take on an M1 phenotype
What is a feature that is common to Alzheimer’s and Parkinson’s disease and frontotemporal dementia?
microglia activation
