neuro-immunology

Question 1

what are the different pathways that are activated by the complement system?

Answer 1

CLASSICAL:
- produces C1q (opson)

LECTIN:
- C4 cleaved by proteases/convertases
- forms opson and anaphylatoxin 
——> opson bind to membranes for “eat-me” signal
——> anaphylatoxins work via GPRCs

ALTERNATIVE
- C3 cleaved by C4bC2b into C3b and C3a

EXTRINSIC
- C5 and C3 cleaved into by-products
- results in formation of MAC attack complex
——> cell death and lysis via MAC

Question 2

how do opsonins functions?

what are the opsonin coaters?

Answer 2

1) foreign cells / damaged neurons express foreign proteins which are marked by IgG
2) astrocytes / microglia release opsonins (C1q, C3b, C4b) which bind to membranes of marked cells

3) microglia become active:
– change conformation
– up-regulate lysosome
– express antibody / opsonin receptors

Question 3

what are anaphylatoxins and what do they do?

Answer 3

anaphylatoxins = potent inflammatory mediators

C5a —> CD88 (GPCR) and C5L2 receptors
C3a —> C3aR (GPCR)

By binding to surface receptors, C3a and C5a mediate:
• recruitment and release of inflammatory cytokines
• degranulation of mast cells

Question 4

how does the MAC complex cause cell lysis

Answer 4

• C5b, C6 and C7 trimer bind to pathogen membrane via C7
• C8 binds to complex and inserts into membrane
• C9 binds complex and polymerises to form a pore in the membrane i.e. the MAC pore
• allows free diffusion in/out of cell —> leads to cell lysis and death

Question 5

describe how C3a-C3aR signalling is both protective and inflammatory

Answer 5

C3a binds to C3aR –> connected to Gi protein

Activates cascade:
– PI3K
– MAPK
–––> AP-1 induces transcription of IL-10
–––> MAPK APK2 –––> NF𝛋B induces transcription of IL-1 and TNF-⍺

INFLAMMATORY:
• activation of C3aR promotes cytokine release (TNF-alpha, IL-1, etc)
• these cytokines promote chemotaxis (cell migration) and proliferation of immune cells

PROTECTIVE:
• using mouse models, it was discovered that an absence of C3aR worsened motor neuron disease (MND) symptoms —-> C3a-C3aR signalling must be protective
• C3aR found on astrocytes
• astrocytes release growth factors when C3a activates
• this promotes neuronal survival

Question 6

describe how C5a-CD88 signalling is inflammatory

Answer 6

C5a binds to CD88 receptor –> connected to G⍺2i protein

Activates cascade:
– PI3K
– MAPK
–––> AP-1 induces transcription of IL-10
–––> MAPK APK2 –––> NF𝛋B induces transcription of IL-1 and TNF-⍺

INFLAMMATORY:
• C5a is made by motorneurons, and is up-regulated is times of stress (near death)
• CD88 (C5a receptor) present on microglia and also motorneurons
• activation of CD88 increases migration and proliferation of immune cells, e.g. neutrophils
• activates caspase-3 to induce neuronal apoptosis

Question 7

what are peri-neuronal nets?

how to they protect synapses?

Answer 7

peri-neuronal nets are extracellular net around excitable neurons, proximal dendrites and inhibitory synapses
– CSPG membrane receptor connects to nets to neuron

PROTECTION OF SYNAPSES:
• form a barrier around synapses to protect from degration
• opsonins released by activated astrocytes and microglia) tag PNN to aid in their destruction by microglia
• additional breakdown of PNNs by CD88 mediated production of MMP9 – a protease that breaks PNNS

destruction of nets can lead to autism, schizophrenia, etc, where there is an imbalance between excitation and inhibition of neural inputs

blocking of CD88 can prevent MMP9 from destroying PNNs and thus preserve motorneurons