Innate immunity: Cell migration Flashcards
What do some tlrs do upon ligand protein
Homo or heterodimerize
Then bind pamp = intracellular
What does dimerization trigger
Activation of adaptor proteins = myd88 trif
Phosphorylation or sometimes ubiquitination
Describe effect of tlrs dimerization - ultimately
Activation of diff tfs
Translocation into nucleus
Expression of diff genes
Name 3 effects of prr signalling
Cytokine production
Increased expression of costimulatory molecules
Enhanced migration to regional secondary lymphoid organ
Describe cytokine production
Il-1 il-6 Il-18, TNF alpha, il-2= inflammation, pro inflammatory cytokines
Type 1 ifn, ifn alpha, ifn beta = post net antiviral effects
Chemokine production
Describe chemokine production
Lead migration of cells to site of infection
Cc chemokines = ccl2 and cxc chemokines = cxcl 8 or Il-8
Different in their location of 2 cysteine residues
Describe increased expression of co stimulators molecules
B7.1 (CD80) b7.2 (CD86)
= provide signal 2 to T cells in secondary lymphoid tissue = recall 3 signals needed for T cell activation
Describe enhanced migration to regional secondary lymphoid organ
Upregulation of specific adhesion molecules
Or can migrate to site of infection
Describe type 1 ifn signalling - process
Has antiviral effects
Ifn secreted upon prr signalling = binds receptors on surrounding cell =
Triggers signalling
More transcription —> these genes inhibit viral replication = can halt/slow virus infection
Describe type 1 ifn signalling - effects
Proteins created = inhibit translation, degrade mRNA, inhibit virus transcription and assembly
= effects viral life cycle
Describe migration
Enhanced migration to secondary lymphoid organ
Triggered by prr signalling
Targeting of dendritic cells to lymphoid tissue
Describe co stimulation
Upregualtion = increase expression
APCs delivers signal to T cells = signal 2 - survival, b7.1 and b7.2 = CD80 and CD86
What are chemokine receptors
Ex of G protein coupled receptors
Transducer signals via interactions with gtp/gdp binding G protein
Chemokines bind recpetor = gdp removed and gtp added = leads to signalling
Can only one receptor bind to one chemokine
NO
Many receptors can bind to more than one chemokine = several chemokines are able to bind more than one recpetor
What do chemokines do
Direct leukocyte migration —> chemotaxis
Signalling through chemokine receptors helps cells move to dif areas
How do cells move to diff areas
Chemokines = cause
Change in adhesiveness, changes in cells cytoskeleton, allow migration to take place
Induce movement of leukocytes, up a chemokine concentration gradient, travel to higher conc chemokines
Describe answer: You discover that a new virus blocks TLR3 signaling by preventing the nuclear translocation of the IRF3. You decide to further study this virus’ impact on TLR3 signaling. What are you most likely to find in a monocyte infected with this virus?
High levels activated irf3 in cytoplasm
Bc tfs in cytoplasm
Signalling from a prr results in their activation
One tfs activated= translocation to nucleus, but cannot translocate, everything upstream =fine
Describe covid and type 1 interferon
3.5% of patients with life threatening covid 19, Had a genetic deficiency = cannot Make type 1 interferon
10% of patients with life threatening covid 19 had neutralizing auto antibodies against type 1 ifn
Describe all steps of inflammatory response
1= breach epi layer
2= bacteria enters body
3= resident innate immune cell, prr binds pamp
4=phagocytosis
5=cytokine and chemokines released = inflammation and vasodilation, recruit cells = 4 hallmarks inflammation
What is recruited to site of infection
Monocytes
Describe whole process of recruiting monocytes
Reunited by adhesion molecules
1= binding of adhesion molecules on endothelial cell and monocyte
2= chemokine binds
Leads to intracellular signalling= can change conformation of adhesion molecules= so binds other adhesion molecule on endothelial cell = anchored now
Then can migrate to tissue
Describe adhesion molecules
Diff fams = selectins, integrins, immunoglobulin superfamily
Diff tissue distribution
Are all adhesion molecules always expresssed
Nooo
Some expressed at baseline
While others only expressed when infection = upregulated (allows cells to migrate to site of infection)
What do leukocytes do
Roll along vascular endothelium
Weak interactions with adhesion molecules
Describe recruitment of leukocytes
Monocytes - precursor of macrophages, neutrophils and other leukocytes recruited to site of infection
= casues heat, redness, swelling, edema
What happens when severe or chronic inflammtion
Arthritis or loss of function
Inflammation should always be acute
Name all migration steps in order
Rolling adhesion
Tight binding = anchoring
Diapedesis
Migration
Describe diapedesis
Process by which a cell crosses from the lumen of a vessel between endothelial cells into the surrounding tissue (site of infection)
Describe migration
In direction of higher chemokine concentrations
