Flashcards in "Microbiology/Immunology Development of B Cells" MARY Deck (26)
T/F: The clonal selection theory states that each naive B-cell produces an immunoglobulin of unique specificity.
True. ONE antibody produced by ONE B-cell, if it survives the process of making the antibody at all.
The J region is also known as:
the Joining gene segment, part of the gene "choices" for the developing B cell's heavy chain (Hc).
The D region is also known as:
The Diversity segment, part of the gene "choices" for the developing B cell's heavy chain (Hc).
The components of Hcs (heavy chains) consist of what segments?
V (variable), D (diversity), J (Joining) and C (constant).
What special enzymes bring together the V, D and J regions in the creation of the Hc?
The recombinase genes Rag 1 and Rag 2. This is important.
T/F: Every heavy chain has a signal sequence section that can join to every light chain that is made, helping to contribute to the large diversity of immunoglobulin products.
False! Each immunoglobulin chain has signal sequences, and those signal sequences determine which other chains it can match to. If a maturing B-cell has made a Hc that does not match the Lc it has made, the B-cell is useless and commits suicide.
Give the overall steps in the maturation of B-cell, from early pro-B-cell to immature B-cell.
1. Early pro-B-cell - rearrangement of D and J regions on both chromosomes.
2. Late pro-B-cell - H chain rearrangement --> V-DJ rearrangement on 1st chromosome
2a. If successful, becomes pre-B-cell
2b. If Step 2 unsuccessful --> V-DJ rearrangement on 2nd chromosome
2c. If successful, becomes pre-B-cell. If unsuccessful, apoptosis
3. Pre-B cell - rearrange K on 1st chromosome --> if successful, done! and B-cell expresses miu and k, IgM is done!
3a. If unsuccessful - rearrange K on 2nd chromosome --> if successful, done! and B-cell expresses miu and k, IgM is done!
3b. If still unsuccessful with both k's, pre-b-cell rearranges lambda on 1st chromosome, if successful, B cell shows IgM with miu and lambda!
3c. If still unsuccessful, pre-b-cell tries to rearrange with lambda on 2nd chromosome, if successful, B cell shows IgM with miu and lambda!
3d. A tired and discouraged pre-b-cell commits suicide if neither k's nor lambdas fit.
Joining of D and J is imprecise, and there is also a special mechanism to increase diversity at the CDR3 site. Explain the steps which create junctional diversity, starting with the cleaving of the RSS (recognition signal sequence) heptamer.
1. The cleavage of both D and J region heptamer RSS's *by RAG complex* creates DNA hairpins.
2. RAG then opens the hairpins on the extruding DNA, yielding "P" palindromic sequences.
3. TdT (terminal deoxynucleotidyl transferase) adds N nucleotides are added randomly to spice things up.
4. The strands with their P section and new N section pair.
5. The non-matched N nucleotides are removed by an exonuclease.
6. Any remaining gaps (for example, over the P section) are filled in by DNA synthesis and ligation, yielding a unique P-N-P junctional site.
Where are N nucleotides found in antibodies?
Only in heavy chains, and they are only found in the developing B-cell, up to the pro-B-cell stage.
T/F: Joining of D to J and V-D in Hc gene formation can involve multiple reading frames, as most Ds can be read in all three reading frames.
A B-cell that has never encountered its cognate antigen is considered:
Naive or virgin. A B-cell that has met and joined with its cognate antigen is considered "experienced" ;)
What are the three routes a B-cell can pursue if it matures?
1. Class switching
2. Somatic hypermutation
3. The "career decision" when a B-cell can become an antibody factory (plasma cell) or a memory cell.
What determines the class of an antibody?
The constant region of its heavy chain (Fc), the "tail" of the Ab. *Therefore, class switching involves the changing of this constant region.
When naive B-cells are first activated, they mainly make antibodies of what class?
IgM, probably the first class of Abs to evolve, even found in lower vertebrates.
What might be the advantage to having IgM be produced first in an infection?
Because IgM is like 5 IgGs together, a big snowflake of a molecule, it has a higher chance of activating the complement cascade or "fixing complement." IgM does this through bringing C1 complexes close together so their inhibitors fall off and they can be activated (complement chain reaction of sorts on the surface of the invader).
Additionally, IgMs can bind to virtually any surface of a virus, preventing its entry into cells.
What are some advantages that IgG antibodies have over IgM?
1. Subclasses of IgG, based on the Fc region, that further specialize their function
2. Can cross the placental barrier and provide fetus with early protection.
3. Longer half life than IgM (3 weeks vs. 1 day)
IgG antibodies are also called:
What is generally considered the most abundant class of antibody in the human body?
IgA! IgG is usually the most abundant class in the blood, however IgA guards the mucosal surfaces (digestive, respiratory, reproductive) of the body and exists in abundance, more than all other classes combined.
IgA is also helpful to the neonate because it is secreted in breast milk.
What is the main influence of class switching for B-cells?
Certain cytokines or combinations of cytokines influence a B-cell to switch from one class to another.
How can the right cytokines "magically" be present for a B-cell to get the correct class-switching instructions?
T-helper cells make these cytokines, more on this in the next lecture.
What is different between the B-cell that is displaying its winning Ab and the Ab it secretes?
As the B-cell becomes an antibody factory, the transcripts exclude the transmembrane domains so the Ab can be free in the blood.
Conversion to what class of antibody does not involve class switching from IgM, and why?
IgD, because this is a simple RNA splicing of the IgM and IgD constant regions, the same way that displayed Ab and secreted Ab are spliced differently.
It should be noted here that the function of IgD is not well understood, if it has a function at all.
What is the all-star enzyme involved in class switching AND somatic hypermutation? Dr. Taffet indicated there will likely be a test question on this!
AID, activation-induced cytidine deaminase
Talk to me about somatic hypermutation. What's happening and where?
The variable region of the Ab (or Ig in the notes), and only the variable region, is undergoing an unusually high rate of mutation. This is particularly evident in the CDR1 and CDR2 regions, which directly contact residues with the CDR3 region of the antigen. It is influenced by the enzyme AID.
When does somatic hypermutation happen?
Usually after class-switching