Lecture 19 - B cells - Generation of Adaptive Immunity Flashcards
What are B-1 B cells?
Describe:
• Location
• Function
• BCR
Not part of the Adaptive immune response, because they cannot form memory cells
However, can still:
• Make Ab against Ag
• Present antigen
Reside mainly in the pleural and peritoneal cavities
Function:
• ‘Natural Abs’ against carbohydrate Ag
• Thus, part of early ‘innate’ response against infection
(NB natural because they are present in circulation in unimmunised mice)
Compare the origin of B-1 and B-2 B cells
B-1 B cells:
• First produced in the liver of the foetus
• Undergo self-renewal in the periphery
• Persist in adult, making up 5% of B cells
• FL-HSC
B-2 B cells:
• Produced & continually replaced in the bone marrow
• Produced after birth
• BM-HSC
What are the two lineages of B-2 B cells?
- Follicular B cells
2. Marginal zone B cells
Describe Marginal zone B cells
• Location
• Function
Location:
• Reside in the marginal zone of the spleen, as opposed to the follicle
• Largely non-recirculating
Function:
• Early participation in adaptive response
• Limited diversity
• Lower threshold (for activation, proliferation, differentiation)
• Ab responses against common bacterial Ag
Compare the activation threshold for MZ and Follicular B cells
Follicular B cells have a higher activation threshold than MZ B cells
What are the majority of mature B cells formed from?
Follicular B cells
What Ig do Follicular B cells express (in the naïve state)?
IgM & IgD
Compare circulation of MZ and Follicular B cells
MZ: non-recirculating
Follicular: recirculate through lymphoid tissues
Compare residence of MZ and Follicular B cells
MZ: marginal zone of spleen
Follicular: follicle of spleen
Describe the antigens to which B cells can respond
Native molecules: • Proteins • Glycoproteins • Polysaccharides • Viral particles • Bacteria
What are the effector functions of B cells?
Ab production:
• C’ activation
• Neutralisation
• Opsonisation
Describe differentiation of B cells after clonal selection & proliferation.
Into which cell types do the clones differentiate?
On what does this differentiation depend?
- Pool of clones
- Differentiate into:
• Memory cells
• Plasma cells
Differentiation depends on the signals the GC B cells receive, which induce either BLIMP-1 or other transcription factors
If the B cells expresses BLIMP-1 it will differentiate into a plasma cell
Which signals does a naïve B cell require to differentiate into an effector cell?
- Cognate antigen
- Activation signal (Tfh cell):
• CD40L-CD40
• ICOS-ICOSL
• IL-21
Describe linked recognition
Why is this important?
Requires both B and T cell to respond to a foreign cognate antigen for the generation of an immune response against it.
This process is very important for self-tolerance, as it is very unlikely that both a CD4+ T cell and a B cell will be autoreactive
- B cell encounters Ag (viral coat protein) w/ surface bound Ab
- RME of Ab+Ag; Ag processing
- Presentation of an epitope of this Ag on MHC class II
- Tfh cell recognises cognate antigen on MHC II w/ its TCR
- T cell help for B cell:
• CD40-CD40L interaction
• ICOSL-ICOS
• Cytokines (IL-21) - B cell forms a germinal centre and make high affinity Ab against Ag (viral coat protein)
How does native antigen get to naïve B cells?
FDCs: Follicular dendritic cells
- Opsonised and C’ covered antigen enters LN via afferent lymphatics
- Macrophages in Sub-capsular sinus bind Ag w/ their C’ receptors
- Ag not endocytosed; maintained on surface of macrophage
- Ag transported into follicle & bound by Follicular DCs with CR1/2
- B cells encounter the antigen on the FDC and become activated
What is a mature B cell?
Developed in the bone marrow and has gone out into the periphery
Is yet to encounter antigen
(For T cells, they are called naïve T cells)
Which type of B cells have direct contact w/ the blood in the spleen?
MZ B cells
Compare antigen composition in T-dependent and -independent Ab responses
T-independent • Polysaccharide • Lipid • Cross linking of Ag to Ab on the cells surface • Production of Ab
T-dependent:
• Protein
What does cross-linking of Ab and Ag on the cell surface affect?
It affects signal transduction in the cell
It improves the response
What type of cell are FDCs?
What is their major function?
- Non immune cells - don’t come from the lineage in the BM
- Takes the shape of an immune cell
- Nothing to do with DCs
They are a “depot for antigen”
They bind C’ bound foreign, native antigen on their surface with CR-1 and CR-2 for recognition by naïve B cells in the follicle
How do B cells and T cells know where to reside?
Chemokine gradients
Cells have receptors on their surface that allow them to follow chemokine gradients into their respective locations
T-cell zone (paracortex):
• CCR7 receptor on T cells recognise:
• CCL19 & CCL21 bind to CCR7
B cell zone :
• CXCL13 expressed here
• CXCR5 expressed on B cells
Describe how naïve T cells and mature B cells encounter each other in the lymph node
- B cell begins to express CCR7 (as well as CXCR5)
- T cell begins to express CXCR5 (as well as CCR7)
- The cells are attracted to the boundary of the follicle and the T cell zone
Which chemokines are present in the T cell zone?
CCL19
CCL21
Which chemokines are present in the B cell zone?
CXCL13
What is the receptor for CXCL13?
CXCR5
What is the receptor for CCL19?
CCR7
Also for the receptor CCL21
What is a plasmablast?
When does this occur?
Some B cells that were stimulated by Tfh migrate to form a primary focus
Here, plasmablasts develop
Plasmablasts produce low affinity IgM which serves as initial humoral immunity
Describe the events directly after B cell interaction with Tfh at the boundary of the follicle and the T cell area
Either:
- Differentiation into plasmablast
or
- Migration back into a follicle to form a GC
Exposed to AID:
→ CSR
→ SHM
Describe the processes that occur within the germinal centre
- Exposed to new enzyme: AID
- SHM: introduction of mutations into the variable region
- CSR: rearrangement of the heavy chain
Differentiation:
4a. Memory cells
4b. Plasma cells
What is the difference between SHM and affinity maturation?
SHM: AID introduces mutations into the DNA coding for the variable region of the Ab
Affinity maturation: selection of the mutated Ab that now has increased affinity for the Ag
What is ‘Secondary diversification’?
SHM in mature B cells during the adaptive immune response
Is CSR reversible or irreversible?
Irreversible
Once switched from IgM to IgG, it is impossible to go back to IgM
Which classes of Ab are likely to be present if someone is vaccinated against a specific Ag?
IgG and IgA
i.e. have undergone CSR
Describe germinal centres
• Activated, clonal B cells that have been stimulated by Tfh undergo rapid proliferation and maturation events
“Island of rapid proliferation amongst non-proliferating, resting B cells”
- Exposure to AID
- Location of secondary diversification (CSR and SHM)
Suggest a reason why naïve lymphocytes are difficult to activate on their own
To prevent activation against the wrong thing (auto-antigen)
e.g. Linked recognition required for B cell activation
This helps to ensure self-tolerance, because an autoimmune response will only occur if both a self-reactive T cell and a self-reactive B cell are present at the same time
What is the function of S1P1?
Receptor on lymphocytes that retains them in lymphoid organs in the early stages after activation
Differentiate between primary and secondary lymphoid follicles
Follicles are the region in secondary lymphoid organs where B cells are localised
Secondary lymphoid follicles have germinal centres, while primary ones don’t
What is the effect of CSR?
Generation of Ab with the same specificity, but with different effector function
What happens to B cells once they encounter their cognate antigen (on FDCs)?
Upregulation of CCR7
Where do T cells reside in the spleen?
PALS: peri-arteriolar lymphoid sheath
