Lecture 15: B Cell Activation and Antibody Production II Flashcards
What results in the formation of mRNA for the membrane or secreted form of the u (mu) heavy chain
Alternative processing of primary RNA transcript
What results in an increasing fraction of the u protein produced as a secreted form
Ag activation of B cell
What are required for somatic hypermutation of Ig V genes to occur
Tfh cells and CD40:CD40L interaction
Where does affinity maturation occur
In the germinal center
Affinity maturation is a process that occurs through
A repeated process of somatic hypermutation of B cell receptors and subsequent clonal selection
Hypermutation can occur where (on gene)
Anywhere along the VDJ region of Ig genes
Can be heavy or light chains or both
What is expressed by B cells that initiates somatic hypermutation in the GC, and how does it work
AID
Induces cytosine to uracil deamination
-This is a mismatch that can be repaired by base excision
Where do Ig V genes undergo point mutations at a very high rate
In the dark zone of the GC
Can occur at an average rate of almost one per cell division
Can Ig V mutations continue to occur in progeny of B cells
Yes, any B cell clone can accumulate more and more mutations during its life in the GC
IgG vs IgM # of mutations
IgG has many more mutations
Mutations correlate with
Increased Ab affinity for Ag that induced response
Why do B cells with highest affinity for Ag have selective advantage
Because they are more likely to bind Ag on FDC which will rescue them from apoptosis
Where is a site of tremendous apoptosis
Germinal center, because somatic mutation also generates many B cells that do not express high affinity Ag receptors and die
Where do B cells migrate after somatic hypermuation
FDC-rich light zone of the GC
Reasons that high affinity B cells survive
- Binding to Ag induces increased expression of anti-apoptotic protein Bcl2
- High affinity B cells will endocytose and present Ag for Tfh cells in GC and induce CD40:CD40L signaling
- Expression of endogenous inhibitors of Fas may occur in high affinity B cells that have bound Ag on BCR
What is a primary cause of B cell lymphomas
Translocation of various oncogenes into Ig gene loci
-DNA breaks associated with somatic hypermutation and isotype switching facilitate these translocations
Isotype switching primarily occurs where and is facilitated by who
Germinal centers facilitated by Tfh cells
Some isotype switching my also occur where and facilitated by
Extrafollicular foci, driven by extrafollicular Th cells
Antibody specificity is determined by what region of the Ig chains
Variable regions
Intracellular pathogen leading to IgG switching- how does this happen
Intracellular pathogen activate Th1 cells which make IFN-y, which also likely induces IFN-y+ Tfh cells to make more IFN-y
IFN-y induces IgG switching
Helminth leading to IgE switching
Helminths likely influence Tfh cell differentiation in to IL-4+ Tfh cells which produce Th2 type cytokines like IL-4 to induce IgE switching
B cells in mucosal areas would likely switch to what Ab class- and what would cause this
IgA switching, caused by TGF-b produced by many cells including Treg cells and macrophages