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39 Cards in this Set

  • Front
  • Back
2 major pathways of B-cell activation
- B-cell receptor (surface Ig) activation
2) T-cell CD40L stimulates CD40 on B-cells
*** Optimal activation requires both!
T-cell dependent vs. independent pathways
- Dependent - typically protein, involve CD40 signal from T-cell
- Independent - typically polysaccharides, activate B-cell directly
B-cell signalling elements
- Surface Ig (sIg)
- Igα and Igβ = actually signal cytoplasm when sIgM stimulated
- CD45 - tyrosine phosphatase - activates src family tyrosine kinases
- Tyrosine kinases = Btk, Blk, Fyn, Lyn
- Co-receptor complex = CD19, CR2/CD21, CD81
Ig cross linking response
- Bacterial cross-linking activates several IgM's together in an area
- Aggregation of signal leads to strong response
- Activation, proliferation, Ig secretion
Immuno Tyrosine Activation Motifs (ITAM)
- Seen in both B- and T-cells
- Igα and Igβ come together, get phosphorylated by tyrosine kinases (Blk, Fyn, Lyn)
- Phosphorylated ITAMs recruit more kinases - set off cascade
Agammaglobulinemia
- Lack of Igα, can't ever properly get activation of B-cells
Co-receptor purpose
- Enhance B-cell signalling
- CR2/CD21 - binds C3 fragments
- Presence of complement, CD21 activation -> lowers threshold for B-cell response
- CD19 = signalling chain
- CD81 = function unknown
Phosphorylation of ITAM purpose
- Set off signal cascade -> activate transcription factors
- Proliferation and Ig production
CD40 signalling mechanism
-CD40L (T-cell) binds CD40
- Activates NF-κB (IκB phosphorylated, degraded -> NF-κB activates genes)
2 CD40 signalling unique factors
1) Required for Ig switching
2) Essential for germinal center response!
- Can't get germinal center response with only Ig receptors!
Hyper-IgM syndrome
- No CD40 produced, only responses via IgM
- No germinal center response
B-cell pathway in body when on the prowl
- Enter lymph nodes via High endothelial venules (HEV)
- Look for Ag's
- If nothing -> leave via lymphatic duct -> back to blood
B-cell activation in lymph nodes
- Finds Ag, looks for T-cell to interact with
- CD40/CD40L interaction -> activates B-cell
- Proliferates
- Some -> germinal centers to continue proliferation
- Others -> plasma cells -> bone marrow
2 activated B-cell pathways
1) Plasma cell pathway -> immediately make Ab
- Tends to be low affinity IgM
2) Germinal center pathway -> Take a while to get going
- Hypermutation, Iso-class switching
- Become plasma cells that produce high-affinity Ab or Memory cells
- Most just die
6 Key features of Germinal center
- Rapidly proliferating clonal B-cells
- Somatic hypermutation
- Ab affinity selection
- Memory B-cells generated
- Isotype switching
- Most germinal center cells die
*** Overall determines long-term outcome of the particular response
Somatic hypermutaion process
- AID converts C -> U in variable regions of Ab
- C bases can mutate to T bases after repair
- Mutations totally random
- Highest affinity matches to Ab survive the longest, rest die
- Natural selection ensures that best matches thrive
Clonal selection purpose/mech
- Only highest affinity B-cells survive, rest die
- B-cells in germinal center continuously taking up, processing, and presenting Ag to T-cells
- High-affinity cells will get enough Ag to present to T-cell
- CD40/CD40L interaction -> B-cell will survive -> most plasma or few memory cells
- No CD40 interaction -> just dies
Affinity maturation
- Achieved when highest-affinity B-cells are selected for
- Overall result of somatic hypermutation and clonal selection
Ag-specific interaction between B- and T-cells
- Germinal centers - recruit cells to come in
- B-cell receptor bind some Ag -> internalizes, processes, presents via MHC II on surface
- Matching T-cell binds
- Gives CD40 interaction -> activates B-cell
- Proliferates, secretes Ig's, etc.
T-cell response to B-cell Ag's
- CD40 response activates the B-cell
- IL4,5,6,21 differentiate newly activated cell -> isotype switch based on needs
- Bind to promoters on cell DNA -> act as transcription factors
IL-4 action
- Promotes G2, G4, E
- Inhibits G1
IFNγ action
- Promotes G1
- Inhibits G4, E
TGFβ and IL-5
- Promote A
Different isotype functions
- G1 = complement fixation, opsonizing
- G3 = Complement fixation, inflammatory
- G4 = neutralizing, poor complement fixation
- A = no complement fixation, mucosal surfaces
- E = binds mast cells -> hypersensitivity
Resting B-cell vs. Plasma cell
- B-cell = expresses surface Ig's, MHC II
- Can proliferate
- Can undergo SHM and CS
- Low rate of Ig secretion
- Plasma cell = no surface markers
- No more differentiation or proliferation
- High Ig secretion
Principle behind vaccination (e.g. tetanus)
Ab block toxins, viruses, and bacteria
- Once Ab's are produced, they bind to epitomes
- Can actually block the action of these, keep them from entering cells, infecting in the first place
Opsonization
- Some Ab's just prime phagocytes for mealtime
Ab-dependent cellular toxicity
- Cells infected with viruses produce weird surface proteins
- Ab's to these will bind them at infected cell surface
- NK cell binds Ab's, destroys cell
Two parts of Ab (besides heavy and light chains)
- variable region - binds Ag, facilitates previous activities
- Fc (constant) region = binds own set of specific receptors
Fc receptor functions
- Bind the other end of the Y-shaped Ig
- Transport IgA across mucosal surfaces
- Transport IgA while breast feeding
- Transport IgG -> fetus across placental barrier
*** Generally facilitate other previous functions as well
Macrophage Fc receptors
- Mediate opsonization
- Allows macrophage to "see" Ab-coated pathogen
Mast cell Fc receptors
- High affinity for IgE
- Ag-bound IgE sets them off
2 Non-immune cells with Fc receptors
- Poly-Ig recptor - epithelial cells
- Brambell receptor - endothelial cells
Poly-Ig receptor function/mech
- Facilitates transport of IgA to/through epithelial mucosal cells
- IgA dimer binds Fc receptor
- Transports through cell to apical surface - keeps it anchored, no washing away
- Can also take IgM through mucosa (via J-chain) in people with no IgA
IgA found in these mucosal tissues
- GI tract
- Respiratory tract
- Tears
- Saliva
- Milk
Brambell receptor function/mech
- Transport IgG from bloodstream to interstitium
- Receptor on endothelium binds IgG, takes it across vessel wall
IgG in utero
- Only Ab to be transported across blood vessels
- Gives fetus some protection
- Lapse after birth until infant makes own IgG
- Supplemented by IgA from breast milk
Titer definition
- Greatest dilution that still yields a positive test
- Measured as ratio (1:20, 1:400, etc.)
- 1:400 means still positive detection when diluted a greater number of times
Paired sera
- Comparison on titers over time
- Rising titer = recent/ongoing infection
- Falling titer = distant past infection