Fichas
B cells
Fichas del conjunto (30)
- 1What is the BCR?- B cell receptor
- Expressed on surface of all mature B cells
- Membrane bound immunoglobulin (same type as rel as antibodies from cell!)
- Controls the activation of the b cell (along w/second & third signal)
- Recog whole antigen (w/out need for it
to be processed) - 2After b cell activation,what happens (basic explanation) ?- Immunoglobulin genes are then
diversified (class switching, somatic mutation)
- B cells then differentiate into:
. Plasma cells that secrete ANTIBODIES (same Immunoglobulin as BCR)
. Long lived memory cells – Recall responses/vaccination - 3How can B cells make enough different antibodies to recognise all possible pathogens?- Generation of antibody diversity – V(D)J
recombination - 4Describe the structure of the b cell receptor/antibody?- Y shaped immunoglobulin
- Transmembrane (receptor) or free (antibody)
- Made up of 2 long heavy chains and
two shorter light chains
- The heavy chains are linked to each other by disulphide bonds + each heavy chain is linked to a light chain by disulphide bonds
- Has a highly variable antigen binding regions made of looping complementary determining regions
- The stem of the Y shape is the constant region - Fc region
- The two top arms of the Y are the variable regions - Fab region - 5What are the variable regions of the light and dark chains of the B cell receptor made up of?- Two or three gene segments -> V, D, J
- V & J = light chain
- V, D, and J = heavy chain - 6What are complementarity determining regions (CDR) ?- Areas on the BCR that determine antigen specificity
- Found at the end of each variable arm of the Y! - 7What is the structure of CDRs?- There are three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively, on the amino acid sequence of a variable domain of an antigen receptor
- Since the antigen receptors are typically composed of two variable domains (on two different polypeptide chains, heavy and light chain), there are six CDRs for each antigen receptor that can collectively come into contact with the antigen
- A single antibody molecule/BCR has two antigen receptors and therefore contains twelve CDRs total
- Some antibodies have more than twelve - IgM is pentameric so has five times the normal amount or CDRs (60) - 8There are two types of light chain in humans, what are they?- Kappa (κ) chain, encoded by the immunoglobulin kappa locus on chromosome 2
- Lambda (λ) chain, encoded by the immunoglobulin lambda locus on chromosome 22 - 9CDR H3 has the most variability, why is this?- Because formed by VDJ combination, incl joining regions - gives upmost diversity as joining regions not always the same - different in every recombination event
- 10What forms CDR H1 and CDR H2?- The V (variable) region - Complementary determining regions held together by framework regions
- Framework regions form the basic domain structure of variable region - the 'hand'
- CDR regions are unstructured loops - 11What mediates recombination of gene segments in VDJ recombination?- Recombination activating genes
- RAG1 and RAG2
- These encode for enzymes RAG-1 and RAG-2
- Joining is IMPRECISE tho! increases diversity in CDRs! - 12What is the 12/23 rule?- V (D)J recombination occurs only between a gene segment flanked by a 12-RSS and one flanked by a 23-RSS
- This is to prevent self-recombination (V w/V, D w/D, etc) - 13What are recombination signal sequences (RSS) ?- Conserved sequences of noncoding DNA that are recognized by the RAG1/RAG2 enzyme complex during V(D)J recombination in immature B cells (and T cells)
- Recombination signal sequences guide the enzyme complex to the V, D, and J gene segments that will undergo recombination during the formation of the heavy and light-chain variable region - 14Only 1 in 3 recombination events are successfuly - why?- The recombined exon must maintain its codon reading frame to make a functional protein.
- Random insertions and deletions will destroy the triplet codon reading frame in 2 out of 3 cases - 15Where do B cells develop/differentiate?- Bone marrow primarily
- Later, the peripheral lymphoid organs such as the spleen - 16As B cells develop recombination of the heavy and light chains occurs in controlled order, which is?- 1st - Heavy chain D-J
- 2nd - Heavy chain V-DJ
- 3rd- Light chain V-J - 17What are the stages of B cell development in order?- Early pro-B cell
- Late pro-B cell
- Large pre-B cell
- Small pre-B cell
- Immature B cell
- Mature B cell - 18What is the bone marrow microenvironment?- Stromal cells line the bone marrow
- Stromal cells = mixture of endothelial, fibroblasts, fat cells
- These cells provide growth signals to developing B cells
- Also provide essential cell-cell contact:
. VLA-4/VCAM-1 (CAMs)
. Kit/SCF
• AND soluble growth factors (cytokines):
. Interleukin 7 - 19At which stage of b cell development is heavy chain rearrangement initiated?- In the pro-B cell
- Occurs when E2A and EBF induce the expression of several key proteins that enable gene rearrangement to occur (incl RAG-1/2) - 20What is TdT?- Terminal deoxynucleotidyl transferase
- A specialized DNA polymerase expressed in immature, pre-B (and pre-T lymphoid cells and acute lymphoblastic leukemia/lymphoma cells)
- Adds N-nucleotides to the V, D, and J exons of the TCR and BCR genes during antibody gene recombination, enabling the phenomenon of junctional diversity - 21What is the pre-BCR?- Composed of two immunoglobulin μ heavy chains and two surrogate light chains, which associate with the signalling molecules Igα and Igβ (Igα/β)
- The production of a functional pre-BCR is the first checkpoint in the current model of B-cell development! - 22What is the surrogate light chain?- Proteins encoded by the VpreB and lambda 5 genes associate with each other to form a light (L) chain-like structure, the surrogate L chain
- 23What does the pre-BCR do?- The newly formed heavy chain gene is tested for functionality by it’s ability to be expressed and bind to surrogate light chain receptor
- If this test is successful -> Pre-BCR signals back into the cell causing:
1. The lambda 5 and VpreB proteins to be no longer expressed.
2. Pre-B cell proliferation
3. Cessation of heavy chain rearrangement (allelic
exclusion)
4. The start of light chain rearrangement
- The best quality Pre-B cell receptors are
expressed at a higher level on the pre-B cell surface and therefore send back stronger signals -> this results in more proliferation ->The best quality pre-BCR out proliferates the others! - 24As there is only a 1/3 chance that VDJ (heavy chain) recombination will be in frame and functional, what happens if it fails?- You have two alleles for the heavy chain so 2nd chance if 1st fails
- 25As there is only a 1/3 chance that VJ (light chain) recombination will be in frame and functional, what happens if it fails?- 2 types of light chain (Lambda and kappa), two alleles of each type so 4 chances for success!
- Happens in regulated order - the first kappa light chain, then the second, then the first lambda light chain, then the second (providing none of the first three succeed) - 26What happens in the transition between small pre-B cell and immature B cell?- At this transition the B cell has a complete BCR on the surface and is tested for self reactivity
- If the BCR recognises antigens in the bone marrow it does not progress to the immature B cell stage (undergoes deletion) - 27What is allelic exclusion?- Ensures mono-specific B cell
- Only one allele of a gene is expressed while the other allele is silenced
- Rearrangement proceeds on one allele first, recombination of the second allele is blocked.
• If this is unsuccessful the second allele rearranges
• If this is unsuccessful the cell dies (heavy chain) - 28How many cells are self-reactive and are therefore not used?- Btwn 25-50%!
- 29There are three potential fates for a self-reactive B cell, what are they?- Death (by apoptosis) - if has strong self recog
- Alive but non-responsive (anergy) - if has weak self recog
- Receptor editing - the cell edits its Ig genes to alter antigen specificity (rare) - 30—
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- Undergrad The Immune System in Health and Disease Fichas sobre B cells, creado por Liberty Grisman-Hughes el 21/04/2022.
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- Liberty Grisman-Hughes
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