Lecture 1- introduction to neuroimmunology Flashcards
what is neuroinflammation?
“The meaning of the term “inflammation” has undergone considerable evolution.
Originally defined by Celsus’ four cardinal signs of “tumor, rubor, calor et dolor” (heat, pain, redness, and swelling), inflammation typically displays extravasation of blood cells.
The word “neuroinflammation,” however, is increasingly used to identify a radically different set of conditions that are specific to the central nervous system (CNS).
The concept of “neuroinflammation” has gradually expanded to also describe diseases that display none of Celsus’ cardinal signs, that do not attract conventional inflammatory cells, and that most neuropathologists would classify as degenerative rather than inflammatory.
These “inflammatory” changes are restricted to a cell type exclusive to the CNS: the microglia.”
what is the central nervous system?
Consisting of the central canal (in the spinal cord) and the ventricles (in the brain)
This reflects the fact that the
mature CNS originates from a
hollow structure in the embryo
called the neural tube
what can Chronic neuroinflammation cause?
can cause collateral tissue damage
what is the lymphatic system?
the thymus, tonsils, liver and spleen
Lymph nodes in groin, neck, armpits and other sites. Critical sites from which lymphocytes are mobilised. Invaders brought back to nodes by antigen presenting cells by lymphatic drainage.
what are the Implications of the discovery of meningeal lymphatic pathways?
Connection between the glymphatic system and meningeal lymphatic vessels. Lymph vessels are shown as thin black lines alongside sinuses and veins. The inset shows how astrocytic vascular endfeet create a distinct perivascular space in the CNS.
what are the immune cells of the CNS, microglia derived from?
the haematopoietic progenitors in the embryonic yolk sac
Under homeostatic conditions, the brain hosts several heterogenous populations of myeloid cells. what does that mean?
Myeloid cells execute homeostatic and surveillance tasks.
Microglia found in intra-neuronal space (a)
Macrophages found in the outer borders of the brain such as the choroid plexus (b),
perivascular space (c) and in the meninges (d).
Blood-derived dendritic cells (e) are present at low numbers in the same locations
as macrophages.
what are microglia?
Microglia are the unique resident macrophages of the CNS parenchyma
~5–10% of the adult brain cell population
Distinct compartment of macrophages that are long-lived and/or locally self-renewing
Ramified morphology with a small, round soma and numerous branching processes
A number of pathologic events, including altered neuronal function, infection, injury and inflammation, rapidly activate microglia.
Activated microglia change from a ramified to an amoeboid and secrete cytotoxic (IL-1, IL-6 TNF-α, ROS and RNS, proteolytic enzymes) factors.
what are Steady-state microglia and homeostasis in the CNS
Resting phenotype characterized morphologically by extensively ramified processes that perform continuous surveillance of their surroundings in the CNS
in vitroexperiments show microglia can secrete neurotrophic factors, such as insulin-like growth factor 1 (IGF1), brain-derived neurotrophic factor (BDNF), transforming growth factor-β (TGFβ) and nerve growth factor (NGF)
Synaptic pruning by microglia has been suggested to be required for normal brain development
Phagocytose apoptotic cells during development
when cells are produced in excess
Shape neural circuits
how are microbial cells activated?
As the main cells of innate immunity of the CNS, microglia constitutively express the most important receptors (MHC I and II, chemokine receptors) at low levels
Activated microglia turn on MHC class II expression, which is required for activation of naive T cells, and produce numerous pro-inflammatory cytokines, including cytokines that induce the differentiation of effector T cells
However, prolonged or excessive microglial cell activation may result in pathological forms of inflammation that contribute to the progression of neurodegenerative diseases
what do microglia express?
pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPS) found on bacteria and viruses
what is the Crosstalk between activated microglia and astrocytes?
Can result in the amplification of inflammatory responses - production of neurotoxic factors.
LPS-induced secretion of factors such as IL-1β and TNF by microglia can result in potent induction of pro-inflammatory gene expression and CSF1 production by astrocytes.
Astrocyte-derived pro-inflammatory factors can feed back on microglia to promote further microglial cell activation, thereby establishing a positive feedback loop
Co-cultures of microglia and astrocytes stimulated with LPS produce significantly more neurotoxic factors than either cell type alone
what are Neurotoxic reactive astrocytes induced by?
activated microglia and are present in neurodegenerative disease
