B cell Diversity Flashcards
Where are B cell first made?
Liver of foetus at 8-9 weeks
What variation of light chains are there?
Lambda and Kappa
How many constant regions are there in the LC and HC?
4-5 in lambda
1 in kappa
9 in HC
Which chain has the D gene segment in B cells?
Heavy chain
What happens in heavy chain recombination?
DJ recombine first
Then V recombines with DJ
What is needed to recognize antigens?
Mostly, HC and LC are required
Exception = some antibodies can recognize with only HC or HL (only 3CDRs needed)
This means it doesn’t matter what the other chain is
What cells do B cell development go through?
Haematopoietic stem cells
MPP
CLP
Pre-B
B cell
How do B cell develop?
MPP recognize FLT3 ligand with FLT3R
Causes differentiation into CLP
VLA4 binds VCAM1 together with IL-7 commits CLP into early pro-B cell lineage = HC DJ recombination giving a late pro-B cell
V recombining with DJ = pre-B cell
VJ recombination of light chain occur in pre-B cell and Ig expressed intracellularly
Immature B cell has Ig expressed on cell surface
Where is FLT3 ligand found?
Bone marrow of stromal cells
What receptor is found in bone marrow stromal cells that CLP binds to?
VCAM1 found on the bone marrow stromal cell
It is bound by VLA4
What chain performs repeated rearrangements?
Light chain loci
How to eliminate autoreactive B and T cells?
T cell = positive and negative selection
B cells = peripheral and central tolerance
Where does central tolerance happen?
Bone marrow
What is positive selection and why does this not happen for antibodies?
This is selecting for cells that recognize your own MHC
Antibodies don’t need to recognize MHC
What is a mature B cell?
Fully VDJ recombined
Light and heavy chain are paired
What happens to immature B cells that have no self reaction? [central tolerance]
Migrate to the periphery to become a mature B cell
What happens to immature B cells that have multivalent self reaction? [central tolerance]
Clonal deletion or receptor editing
Receptor editing only happens in B cells in the bone marrow
What happens to immature B cells that react to soluble self molecules? [central tolerance]
Migrate to the periphery and become anergic B cells
What are anergic B cells?
Cells that persist in the periphery but are unresponsive to antigen
What happens to immature B cells that have low-affinity to self? [central tolerance]
Migrate to periphery to become mature B cell
Clonally ignorant though, don’t bind antigen???
What happens in receptor editing?
B cell development stops and rearrangement of LIGHT CHAIN
New receptor specificity is not expressed
What happens to immature B cells that have no self reaction? [peripheral tolerance]
Becomes mature B cells
What happens to immature B cells that react to multivalent self molecules? [peripheral tolerance]
Apoptosis = NO receptor editing
What happens to immature B cells that react to soluble self molecules? [peripheral tolerance]
Anergic B cell»_space;> Apoptosis
What happens to immature B cells that have low affinity for self? [peripheral tolerance]
Become mature B cells = clonally ignorant
What does final maturation of B cell occur?
When escaped into periphery and passes central and peripheral tolerance = must undergo final maturation step
Where does the final maturation step happen?
Lymphoid follicles in secondary lymphoid organ
Mostly spleen
What are the different types of B cell?
Follicular B cell
Marginal zone B cells
What signals do they receive?
Survival factors = BAFF
What cells produce survival factors?
Follicular dendritic cells
What enzyme initiates somatic hypermutation?
AID = activation-induced cytidine deaminase
Where is AID expressed?
Only in germinal centre B cells
What does AID do?
Deaminates C into U
What repair pathways can be activated to deal with the mismatch?
Base excision repair
Mismatch repair
Transcription coupled repair
What are the outcomes of somatic hypermutation?
Change in affinity, breadth and structural stability of antibodies
Where does somatic hypermutation occur?
Darkzone of germinal center
Where is the germinal centre?
In the B cell follicles of secondary lymphoid tissues
What role do follicular helper T cells play in B cell somatic hypermutation?
B cells mutate their antibody genes in dark zone of germinal centre
B cells w high affinity for antigen can capture and present it w MCH-II
Present it to follicular helper T cells
T cells give survival and mitogenic signals via CD40 and cytokines
B cells that receive help from T cell = can re-enter the dark zone to undergo additional mutation
What dictates the Ig Isotypes?
The constant region of antibodies = in Fc region
What different features do Ig have?
Molecular weight, half life, serum level and half-life in serum
What is needed for an Ig to be transmembrane?
Ig must be hydrophobic = need certain residues
Why is dimerization of IgA important?
Dimerization is required for transport through epithelial cells
When is IgM found as hexamer?
In the plasma without J chain
What is avidity?
Binding strength of entire antibody complex with antigen
Describe the affinity in multimeric vs monomeric antibody
Binding Kon/Koff = higher for multimeric antibodies
Because more energy is required to remove more antibodies
