B cell Activation/ Differentiation/ Memory Generation Flashcards
How many types of antigen receptors does each B cell have?
1 single type- many copies
What describes how upon stimulation, each B cell creates clones of cells with same antigen receptor?
Clonal selection hypothesis
When do B cells make clones?
once activated/ selected for
Where does stem cell maturation into immature committed B cells occur?
Bone marrow
Where does antigen-dependant proliferation/ differentiation into plasma/ memory cells occur?
Peripheral lymphoid tissue
What are B cells that have the BCR but have not encountered antigen called?
Immature B cells
What can mature B cells differentiate into?
memory cells
plasma cells (produce antibodies)
What are the two B-cell responses?
T-dependant = TD
T-independent = TI
What B cell response requires help from T cells?
T-dependent
What B cell response does not require T cell help?
T-indipendent
What B cell response is typically initiated upon antigen recognition?
T-dependent
What B cell response is generated upon exposure to multivalent/ polymerized antigen? (more complex)
T-indipendent
How does a TI-1 antigen bind to B cells?
through PRRs/ mlgs (Ig)
How does a TI-2 antigen bind to B cells?
cross-link large # of BCRs
How many T-independent (TI) forms are there?
2 = TI-1/ TI-2
What is the 3-front attack of the T-dependent B-cell response?
- Directly bind antigen
- T helper cell binds to/ interacts with B cell
- TH cell activated- release cytokines/ activate B cell
How do B cells bind antigens?
BCR
- initial activation/ proliferation
How is some antigen presented on B-cell surface?
some antigen internalized/ processed
- presented on cell surface MHC class II molecules
What does TI-1 antigen bind to?
B cells
What does TI-2 antigen bind to?
Cd3 complement components
cross-link receptors
What receptors is the TI-1 antigen associated with?
Ig and innate
- signalling from both
What is CD21?
complement receptor
What does a T-dependent antigen require to generate an antibody response?
T-cell help
What happens in a T-dependent cell response if you only have B or T cells alone? (mice experiment)
no activation point
What are the 3 steps in T-dependent B-cell response?
- BCR signalling
- Co-stimulatory interaction/ present antigen to TH cell
- Cytokine signalling- activate B cell
What can individual activated B-cells differentiate into?
- entry to germinal centre
- IgM memory cell
- plasma cells (secrete antibodies)
What part of the lymph node is the B-cell zone?
Follicle
What part of the lymph node is the T-cell zone?
Paracortex
For the T-dependent B-cell response why is the antigen endocytosed once bound to BCR?
present to T cells
What are the 2 ways for an antigen to be endocytosed into B cell?
Lysosomal proteases
Actomyosin fibers
What cleaves antigen off surface of APC for endocytosis into B cell?
Lysosomal proteases
What exerts a pulling force on BCR with a high affinity to bring whole antigen/ APC into B cell? (whole BCR)
Actomyosin fibers
What are the 5 steps for BCR antigen endocytosis?
- Polymerization/ close contact
- Pull clusters to centre of contact (inc affinity)
- Initiate uptake
- Enodyctosis with APC fragments
- Endocytosis complete
What induces internalization (endocytosis of antigen by B cell) and antigen presentation?
Antigen receptor clustering
When are BCR-antigen complexes internalized?
endocytosis once signaling begins
How are endocytosed antigen fragments presented on B-cell surface to solicit T-cell help?
MHC class II molecules on B cell surface
What co-receptors are upregulated by antigen engagement? (B-T cell interaction)
CD40/ CD80/ CD86
When are germinal centres formed?
after/ once B cells activated
Where are germinal centres in lymph nodes?
inside follicle (B-cell zone)
Where in the lymph node is the [ ] of activated B-cells?
germinal centre
What are antibody/ Ig-secreting cells?
plasma cells
What is the plasma cell fate of a B-cell?
antibody secretion
What is the germinal centre fate of a B-cell?
SHM antigen-mediated selection
What dictate the fate of antigen-activated B cells?
transcription factors in regulatory network
What transcription factor promote germinal centre B cells?
Pax5/ Bcl-6
When do Pax-5/ Bcl-6 promote germinal centre B cells?
when coupled with low IRF-4 levels
What transcription factor promotes B-cell plasma cell?
BLIMP-1
When does BLIMP-1 promote B-cell plasma cells?
when coupled with high IRF-4 levels
When during the immune response are plasma cells/ Ig-secreting cells found in lymph node?
first 5-6 days
What type of B-cell bears cell surface IgM but does not secrete antibodies?
Naive B-cell
What happens when a naive B-cell interacts with an antigen?
becomes plasmablast
What are AFCs?
antibody-forming cells
= plasmablasts/ plasma cells
What are differentiated B-cells that have begun to secrete antibodies but not yet lost capacity to proliferate?
- still bear cell surface BCRs
Plasmablasts
What prevents free diffusion of lymph fluid into the lymph nodes? (lines the subscapular sinus region)
SCS
- control lymph node structure
What is the relative lag period of Naive vs Memory B-cells?
Naive- longer
Memory- shorter
What is the relative time of peak response of Naive vs Memory B-cells?
Naive- longer
Memory- shorter
What is the relative magnitude of peak antibody response of Naive vs Memory B-cells?
Naive- varies
Memory- strong/ specific
What antibody isotype is produced by Naive B-cells?
IgM
What antibody isotype is produced by Memory B-cells?
IgG/ IgA = class switching
What is the relative antibody affinity of Naive vs Memory B-cells?
Naive- low
Memory- high
What is the relative life span or Naive vs Memory B-cells?
Naive- short
Memory- long lived
Can naive B-cells recirculate?
yes
Can memory B-cells recirculate?
yes
What is SHS?
Somatic hypermutation
- affinity selection
Where does somatic hypermutation occur?
within germinal centre
What produces individual point mutations in Ig-heavy and light chain rearrangements? (variability)
SMS
What increases the affinity of an antibody for an antigen over time?
AID = activation-induced cytidine deaminase
How do SHS point mutations increase?
overtime/ with repeated exposures
What followed by affinity selection results in increased affinity for antigen over time?
Mutations (SHM)
What is enzyme AID induced by?
Bcl-6
What enzyme is responsible for both SHM and CSR?
AID = activation-induced cytidine deaminase
What is CSR?
class switching recombination
What turns down the expression of DNA damage response genes that might interfere with genetic changes generated during SHM?
AID
What happens to B-cells in the germinal centre?
optimation (optimize for future efficient response)
What happens to a B-cell when it enters the germinal centre?
proliferation and SHM (somatic hypermutation)
What is the traditional antibody isotype produced by naive B-cells?
IgM/ IgD
What is the process of expressing any heavy chain class other than IgM/ IgD? (naive ones)
Class switch recombination
Where does class switch recombination occur?
germinal centre
- after antigen contact
What regions does recombination occur between?
donor/ acceptor switch (S) regions
What are the donor/ acceptor switch (S) regions?
tandem repeats of short G-rich sequences
= 20-80 bp long
- contain targeting sites for AID
What contains target sequences for AID (enzyme)?
Switch (S) regions
- repeats short G-rich sequences
What must B cells receive to engage in CSR (class switch recombination)?
costimulatory signals from CD40
What determines what isotype is produced in CSR?
which cytokine signal is received
What are the different isotypes that can arise in CSR (from IgM/ IgD)?
IgG/ IgE/ IgA
What stimulates the transcription of sterile RNAs from germ-line promoters?
Cytokines
What is critical to CSR activity?
sterile RNA
What would happen if no CD40L in T cells?
- costimulatory molecule
not activated- no cytokines produced/ no CSR activity
What cytokine signal can produce class switching to IgG or IgE?
IL-4
What cytokine signal can produce class switching to IgA or IgG?
TGF
What cytokine signal can produce class switching to IgA?
IL-5
What cytokine signal can produce class switching to IgG?
IFN-y
What T-independent B-cell response is associated with bacterial cell wall components?
TI-1
What T-independent B-cell response is associated with capsular polysaccharides?
TI-2
What are the 2 subclasses of B-cells that regulate the T-independent antigen response?
B-1 B cells
Marginal zone B cells
Do T-Independent B cells also go to germinal centre?
no- not same response as T-dependent
What B-cell subclass for TI response produces IgM
“natural antibodies” that bind broad antigens with low affinity?
BI-1 B cells
What B-cell subclass for TI response must receive low-level signals through BCR for survival?
Marginal zone B-cells
What B-cell subclass TI is specialized to respond to blood-borne antigen entering immune system through spleen?
Marginal zone B-cells
What B-cell subtype can renew themselves in the periphery?
Marginal zone B-cells
