Lecture 7/8: Humoral Response/Effectors Flashcards
2 co-stimulators for B cells
- Ag + C3d to CR2
- Ag + PAMP to TLRs
B cell signal transduction path
- Ag -> memb. Ig crosslinking
- Tyr kinase action
- Downstream TF translocation
ITAMs and ITIMs
Immunoreceptor Tyr-based Activating/Inhibiting Motifs
Initial Ab response vs memory response
Initial = IgM, few IgG, low/slow
Memory = IgG, faster/higher/longer
Outcomes post-B cell activation
Not mutually exclusive
1. Increase survival/proliferation
2. Th interaction (Ag presentation)
3. Increase cytokine receptors
4. Migration from follicle to T cell zone (more CCR7)
5. Ab secretion (plasma cell generation)
Localization of class-switched B cells
Memory (long-lived, years):
- IgG: bone marrow
- IgA: mucosal tissue
- IgE: submucosa (resp, GI) + skin
Plasma (short-lived, days)
- IgM: spleen, LNs, mucosa, peritoneal cavity
Cells of the lymph node
DCs, B cells, T cells
Lymph node zonation
DCs from lymphatics, B/T from circulation
T cells: parafollicular T cell zone via CCR7
B cells: follicles via CXCR5
B cell activation + affinity maturation process
1a. DC w/ Ag to T cell zone -> Th recognition
1b. B cell recognizes Ag B cell zone -> migration to T cell zone
2. Initial T-B interaction
3. Extrafollicular focus: Th x plasma cell interaction
4. Germinal center rxn (Ef T/class-switched B move to GC):
- Follicle DC, Tfh, Bgc, memory B, plasma cells -> optimal Abs (B proliferation, class-switch, affinity maturation, somatic hypermutation)
5. High affinity plasma + memory cell exit
Germinal center cells and functions
- Tfh: CD40L, cytokines -> B cell activation
- DCf: special DC -> B cell activation
- B cells: secrete Abs, present Abs -> T cells, MHC II APC to T cells
Ig isotypes and functions
IgM: complement activation
IgG: FcR-based phagocytosis, complement activat., neonatal placenta immunity
IgE: mast cell degranul. (IL-4/-13 C-switch)
IgA: mucosal immunity (epithelial transport)
Mechanism for class-switching
- Activation Induced Deaminase alters Ig DNA, bringing VDJ region close to other Fc regions
- Splicing VDJ to new Fc
- Transcript. + transl. to new Ab
Somatic hypermutation
Process of additional V region recombination in affinity maturation; high affinity B cells are then selected for
Polyclonal vs monoclonal Abs
Polyclonal = typical immune response; multiple clones -> different Abs for different Ags on intruder
Monoclonal Abs derived from 1 B cell clone: no affinity maturation, no difference in Ag detection (consistent response useful for diagnostics/therapy)
Hyper-IgM syndrome
CD40L or AID defects impair class-switching so Abs mostly remain IgM
T dependent vs T independent Abs
Dependent: class-switched, high affinity, memory B cells
Independent: no class-switching, mostly low affinity IgM from short-lived cells; important for non-peptide Ags
What’s the advantage of conjugate vaccines?
Binds peptide Ags to non-protein Ags enabling T dependent activation
What downregulates the Ab response?
Ab-Ag complex binding B cell Ig and Fc receptor -> Ig has ITAM, some FcRs have ITIMs -> blocking BCR signaling; slows Ab production but keeps memory cells
IgG functions
- Microbe/toxin neutralization
- Opsonization
- Classical complement activation
- NK cell ADCC
- Neonatal immunity via FcRn
- B cell activation feedback inhib.
IgM functions
- Classical complement activation
IgA function
- Mucosal immunity
IgE function
- Activate mast cells, helminth immunity
Neonatal Fc receptor (FcRn)
mφ’s, endothelial cells
1. IgG binds FcRn in endosomes
2. FcRn-IgG complexes sorted to recycling endosomes
3. IgG released back to EC space
-> cross-membrane transport
How does IgG stick around for so long?
IgG Fc increases its half life; typically 4-6 weeks with FcRn recirculation
How do Igs neutralize microbes?
Mainly done by IgA
- Blocks penetration of epithelial barrier
- Blocks bind./infection of cells
- Blocks toxin binding to cell receptor
How does Ig opsonization work?
FcRs on phagocyte allow Ig to act as bridge
How does IgG enable ADCC?
IgG binds Ags and NK cell CD16 leading to apoptosis
Th2 secretory functions
- IL-4 -> IgE class switch
- IL-4/-13 -> M2 mφ activation, GI mucus secretion
- IL-5 -> eosinophil activation
IgA function
1st line adaptive immunity for host + newborn
- Poly-Ig receptor binds IgA for transcytosis to secrete to breast milk, lumens
Complement cascade effect
1 enzyme cleaves many more of next component
Complement process
- C3 -> C3a, C3b (inflam., opson.+phagocytose)
- C5a -> inflam.
- C6-9 -> MAC for lysis
Classical activation IgG or IgM
Complement anaphylotoxins
C3a, C4a, C5a: responsible for anaphylactic shock
Complement effector pathway
- Complement binds cell surface
- C3 convertase forms
- C3b binds pathogen (opsin)
- C3a anaphylotoxin - C5 convertase made
- C5a anaphylotoxin
- C5b recruits C6-9 (MAC)
Complement regulation
Multiple regulatory factors:
- C1 inhibitor blocks C1 protease
- Decay Accelerating Factor (DAF) blocks C3 convertase formation
Excess C1 activity -> increased bradykinin -> edema
Complement tickle
Complement is always produced at low levels
Hereditary angioedema periodic swelling
C1 inhibitor deficit
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Decay Accelerating Factor (C3 convertase inhibitor) deficit
