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43 Cards in this Set

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What are the two stages of B-cell development?
Antigen-independent and antigen-dependent.
What are the three major features of the antigen-independent stage of B-cell development?
1. DNA rearrangements (provides diversity)
2. Allelic exclusion (express 1 Ab on surface)
3. Delection of self-reactive clones (tolerance)
Where does the antigen-dependent stage of B-cell development take place?
The three processes of the antigen-dependent phase of B-cell development occurs in the bone marrow and fetal liver
How does the environment of the bone marrow affect B-cell development?
The B-cell progenitor cells associate with the stromal cells in the bone marrow. Adhesion receptors on stromal cells keep B-cells clos throughout their development. Stromal cells also provide survival and development signals that are crucial for B-cell development
What are the crucial growth factors and cytokines provided by the stromal cells of the bone marrow?
Stem Cell Factor (SCF) - which interacts with C-Kit receptor on B-cells
Interleukin 7 (IL7) - survival for B-cells and DNA rearrangements.
In order to achieve allelic exclusion what must occur first?
Ordered rearrangement of Ig genes is the crucial step that must occur to achieve allelic exclusion
What is the progression of B-cell development in the bone marrow?
The HC rearranges first. The first rearrangement is D-J (early pro B-cell), then V-DJ arrangement ( late pro B-cell)of HC. VDJ rearranged (Large pre-B-cell)
What is the probability that rearrangement produces a functional protein?
1/9. 1/3 chace that each rearrangement results in a correct translational reading frame for each rearrangement
What is a functional rearranged heavy chain known as?
Mu heavy chain protein.
What occurs once the Mu protein is formed?
The Mu protein then associates with two surrogate light chain proteins forming a Pre-B cell receptor.
Why is the formation of the Pre B-cell receptor important for B-cell development?
Formation of the Pre B-cell receptor is a critical checkpoint in B-cell development. It will send three important signals to the developing B-cell:
1. Stop rearrangement of other allele of HC gene, ensuring Allelic Exculsion
2. Proliferate
3. Begin LC rearrangement
What happens is the first HC rearranges, but doesn't produce a functional rearranged VDJ segment?
The second allele attempts to complete the rearrangement, if this fails the cell will die
When does the LC rearrange?
Only after a functional HC has been produced.
What are the loci thar rearrange in the LC?
Kappa and Lambda. 4 different alleles of LC genes, two of both Kappa and Lambda.
What is the probability that a functional rearrangement?
1/3 because there is only VJ rearrangement
Which loci rearranges first?
Kappa usually precedes Lambda. Upon sucessful rearrangement of kappa loci LC rearrangement stops.
What is the second checkpoint in B-cell development?
Formation of a functional IgM B-cell receptor, which occurs after successful LC rearrangement. This signals the B-cell to continue to develop and exit the bone marrow
If both alleles of kappa and both allels of lambda fail to rearrange functionally what happens?
The pre B-cell dies. This enforces allelic exculsion.
How does signaling through the BCR occur?
BCR associates with IgA and IgB to provide signaling function. This activates Syk kinases which in turn activates a cascade of TAC tyrosine kinases (BLK, FYN, LYN). TAC kinases activate BTK
What is Bruton's XLA?
A disease caused by mutations in BTK which cause all B-cells to be stuck in Pre B-cell stage
Once the B-cell IgM is produced what happens?
The BCR is tested to ensure that it does not recognize self-antigens before the cell is allowed to exit the bone marrow.
What happens during BCR testing?
If there is no self recognition then the B-cell exits the bone marrow. If the BCR recognizes self it undergoes LC editing in which the the V segments and J segments of the LC are rearranged. If this rearrangement recognizes self it undergoes cell death.
What are the general steps of the antigen dependent phase of B-cell development?
occurs in presence of antigen and T-cells. T-cells signal B-cells to proliferate. T-cell dependent responses are refined via affinity maturation and class switching. This produces plasma cells and memory B-cells
The B-cells released into the bloodstream express what molecules?
IgM and Class II MHC on surface of the B-cell
What is the duration of a naive B-cell in the periphery?
About 3 weeks after which apoptosis occurs
Where do most B-cell/antigen encounters occur?
In spleen and lymph nodes
What is the fate of B-cell/antigen encounters?
T-cell indpendent fate and T-cell dependent fate
What happens in the T-cell indepdent fate of B-cell/antigen encounter?
This occurs in spleen. Causes a rapid proliferation and differentiation into plasma cells in response to carbohydrate or lipid antigen. Results in fast but low-affinity antibody, usally IgM
What happens in the T-cell dependent response of B-cell/antingen encounter?
In the spleen and lymphnodes the immature B-cells traverse the T-cell zone and goes into the primary follicle. Upon encounter with antigen or antigen specific T-cell teh primary follicle becomes a germinal center. Memory cells and plasma cells wiht higher affinity antibodies usually IgG type. Takes 1.5-2wks
The B-cell will present internalized antigen peptide on what type of MHC molecule?
MHC Class II
What are the help signals that are elicited from the T-cell upon B-cell presentation of antigen?
There is both a cytokine and cell-cell interaction response. The CD40 on the B-cell binds the CD40L on the T-cell which sends a signal to the B-cell to develop. IL4 is also released, class switching occurs.
How does the T-cell focus the cytokine release onto the B-cell?
The T-cell undergoes cytoplasmic rearrangement focusing cytokine secretion on the point of CD40/CD40L contact point which is where the cytokine receptors bundle
Where does T-cell help occur?
In the germinal center. The light zone is where follicuar DCs and T-cells reside. The dark zone is the region where B-cells proliferate
What important events happen in the germinal center?
affinity maturation, iso-type switch recombination, peripheral tolerance, maturation of B-cells inot plasma cells or memory cells.
How are higher affinity clones selected?
The selection of higher affinity clones occurs through somatic hypermutation of variable region genes.
What is somatic hypermutation
the production of random mutations in the V region of the BCR, usually involving a single base, which may produce a higher affinity receptor.
What ar the two signals needed in selection of high affinity clones?
1. CD40/CD40L
2. Antigen presented on FDC
What occurs to both low-affinity B-cells and higher affinity B-cells produced during somatic hypermutation?
Low affinity B-cells undergo apoptosis. The B-cells that are altered cycle through the germinal center multiple times and the specificity is refined
What is Iso-type switch recombination?
The changein Ig type on surface of B-cells that is signalled by cytokines from T-cells
What is peripheral tolerance?
This is the elimination of self-recognizing clones.
What is Hyper IgM Syndrome?
An immunodeficiency disease that arises when proper germinal center reactions (somatic hypermutation and isotype switching) cannot take place. So only low affinity IgM molecules are made.
What causes Hyper IgM Syndrome?
Mutation in AID or mutations in CD40/CD40L. Need AID for CSR and CD40/CD40L for cytoplasmic rearrangement and focusing cytokine secretion which leads to class switching
What is the role of plasma cells?
Factories of antibody secretion. They have lots of ER. They secrete switched isotype with high affinity for antigen. They do not divide. Small population of plasma cells remain in the bone marrow producing low levels of antibodies.