Lecture 15 - B Cell Activation and Antibody Production (part II) Flashcards
What is affinity maturation and what causes it?
L15 S8
Somatic hypermutation in Ig V genes and selection fo increased affinity that occurs in the germinal center.
Requires TD (T-dependent) Ag response and interaction with T(fh) and CD40:CD40L
What occurs in the dark and light zones of the germinal center?
L15 S10
Dark zone:
- proliferation
- mutation of V-region
Light zone
-selection of B cells with high affinity by binding Ag on FDC
What is affinity maturation and what causes it?
L15 S8
Somatic hypermutation in Ig V genes and selection fo increased affinity that occurs in the germinal center.
Requires TD (T-dependent) Ag response and interaction with T(fh) and CD40:CD40L
What is the mechanism of affinity maturation and what is the rate of mutation?
L15 S11
B cells express AID which causes cytosine to uracil deamination.
When the B cell undergoes expansion, this damage is corrected in an error-prone manner (base excision and mismatch repair) which can generate new sequences.
A mutation occurs in the variable region roughly once per cell division.
Mutation continues to occur in B cells and mutations accumulate.
What Ig is more prone to mutation?
L15 S13
IgG
How are high-affinity B cells selected for?
L15 S14
B cells that are unable to bind to Ag displayed by FDCs undergo apoptosis.
As Ag becomes less abundant, the B cells with the highest affinity have a selective advantage. Overall there is an average increase in affinity.
B cells can also present Ag to T(fh) cells promoting survival via CD40
What is one of the main factors of inflammation in lymph nodes during an infection?
L15 S15
Because mutation of the V-region can result in B cells that are not high affinity, many B cells undergo apoptosis in the germinal center.
What are the mechanisms of B cell survival in the follicle?
L15 S16
- Ag recognition induces anti-apoptotic protein Bcl-2
- Ag presentation by B cells to T(fh) induces CD40L which binds B cell CD40
- inhibitors of Fas are expressed by Ag recognition
What pathologies can occur due to the hypermutation of B cells?
L15 S17
B cell lymphoma:
-incorporation of oncogenes into Ig gene because of DNA breaks and repair
Autoimmunity:
-somatic mutation can produce self-reactive B cells
How does pathogen type/location and B cell location affect isotype switching?
L15 S20-22
IgG:
-intracellular pathogen activates Th1 cells that produce IFN-γ and stimulates IFN-γ+ T(fh) cells that induce IgG switching
IgE:
-helminths trigger IL-4+ T(fh) which stimulates IgE
IgA:
- mucosal T(reg) cells and Mφ produce TGF-β which stimulates IgA switching
- mucosal DCs and Mφ produce BAFF which co-stimulates IgA switching
Why is CD40:CD40L signaling required for isotype switching and affinity maturation?
L15 S23-25
Isotype switching and affinity maturation are highly dependent on AID expression.
CD40 induces AID
What are the different types of plasma cells and how/where are they produced?
L15 S28-29
Short lived:
-produced by extrafollicular T-independent response or extrafollicular T-dependent response
Long lived:
- produced as plasmablast by T-dependent response in germinal center
- plasmablast home to bone marrow where they become long-lived plasma cells
- survival is maintained by BAFF
What are the fates of long lives plasma cells?
L15 S30
Bone marrow:
- survival
- humoral Ig production
Spleen/lymph node:
- survival (BAFF+)
- humoral Ig production
Inflamed tissue:
-apoptosis after resolution (BAFF-)
What is responsible for memory B cells ability to survive without Ag stimulation?
L15 S33
Expression of anti-apoptotic Bcl-2
What is the mechanism of class-switch recombination (CSR)?
L15 S25
- AID converts cytosine to uracil
- uracil N-glycosylase (UNG) removes uracil residue
- apurinic/apyrimidinic endonuclease (APE1) creates double stranded break
- C genes of Ig are recombined by ligating
