Lecture 7/8: Humoral Response/Effectors Flashcards
(37 cards)
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
