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39 Cards in this Set
- Front
- Back
2 major pathways of B-cell activation
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- B-cell receptor (surface Ig) activation
2) T-cell CD40L stimulates CD40 on B-cells *** Optimal activation requires both! |
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T-cell dependent vs. independent pathways
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- Dependent - typically protein, involve CD40 signal from T-cell
- Independent - typically polysaccharides, activate B-cell directly |
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B-cell signalling elements
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- 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 |
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Ig cross linking response
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- Bacterial cross-linking activates several IgM's together in an area
- Aggregation of signal leads to strong response - Activation, proliferation, Ig secretion |
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Immuno Tyrosine Activation Motifs (ITAM)
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- 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 |
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Agammaglobulinemia
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- Lack of Igα, can't ever properly get activation of B-cells
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Co-receptor purpose
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- 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 |
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Phosphorylation of ITAM purpose
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- Set off signal cascade -> activate transcription factors
- Proliferation and Ig production |
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CD40 signalling mechanism
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-CD40L (T-cell) binds CD40
- Activates NF-κB (IκB phosphorylated, degraded -> NF-κB activates genes) |
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2 CD40 signalling unique factors
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1) Required for Ig switching
2) Essential for germinal center response! - Can't get germinal center response with only Ig receptors! |
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Hyper-IgM syndrome
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- No CD40 produced, only responses via IgM
- No germinal center response |
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B-cell pathway in body when on the prowl
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- Enter lymph nodes via High endothelial venules (HEV)
- Look for Ag's - If nothing -> leave via lymphatic duct -> back to blood |
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B-cell activation in lymph nodes
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- 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 |
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2 activated B-cell pathways
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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 |
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6 Key features of Germinal center
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- 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 |
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Somatic hypermutaion process
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- 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 |
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Clonal selection purpose/mech
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- 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 |
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Affinity maturation
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- Achieved when highest-affinity B-cells are selected for
- Overall result of somatic hypermutation and clonal selection |
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Ag-specific interaction between B- and T-cells
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- 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. |
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T-cell response to B-cell Ag's
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- 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 |
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IL-4 action
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- Promotes G2, G4, E
- Inhibits G1 |
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IFNγ action
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- Promotes G1
- Inhibits G4, E |
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TGFβ and IL-5
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- Promote A
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Different isotype functions
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- G1 = complement fixation, opsonizing
- G3 = Complement fixation, inflammatory - G4 = neutralizing, poor complement fixation - A = no complement fixation, mucosal surfaces - E = binds mast cells -> hypersensitivity |
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Resting B-cell vs. Plasma cell
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- 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 |
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Principle behind vaccination (e.g. tetanus)
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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 |
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Opsonization
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- Some Ab's just prime phagocytes for mealtime
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Ab-dependent cellular toxicity
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- 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 |
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Two parts of Ab (besides heavy and light chains)
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- variable region - binds Ag, facilitates previous activities
- Fc (constant) region = binds own set of specific receptors |
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Fc receptor functions
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- 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 |
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Macrophage Fc receptors
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- Mediate opsonization
- Allows macrophage to "see" Ab-coated pathogen |
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Mast cell Fc receptors
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- High affinity for IgE
- Ag-bound IgE sets them off |
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2 Non-immune cells with Fc receptors
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- Poly-Ig recptor - epithelial cells
- Brambell receptor - endothelial cells |
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Poly-Ig receptor function/mech
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- 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 |
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IgA found in these mucosal tissues
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- GI tract
- Respiratory tract - Tears - Saliva - Milk |
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Brambell receptor function/mech
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- Transport IgG from bloodstream to interstitium
- Receptor on endothelium binds IgG, takes it across vessel wall |
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IgG in utero
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- 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 |
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Titer definition
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- 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 |
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Paired sera
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- Comparison on titers over time
- Rising titer = recent/ongoing infection - Falling titer = distant past infection |