Activated B cells and how they change it up Flashcards
what is Bruton’s tyrosine kinase deficiency?
Brutons disease or X-linked agammaglobulinemia
- low or completely absent Igs in blood
- Btk gene is on the X-chromosome
what are the effects of Bruton’s tyrosine kinase deficiency?
-Btk phosphorylates and activates PLCg2
Absence causes
- No proliferation of B cells
- No activation of B cells
- No mature B cells
what are the symptoms of Bruton’s tyrosine kinase deficiency?
Frequent infections, delayed growth
what is the treatment for burton’s tyrosine kinase deficiency?
regular intravenous gamma globulin, prompt treatment of any cuts/infections
what is Igalpha deficiency?
agammaglobulinaemia
- this is not X-linked
what are the symptoms of Igalpha deficiency?
frequent infections, delayed growth
what is the treatment for Igalpha deficiency?
regular intravenous gamma globulin, prompt treatment of any cuts/infections
what are the four phases of B cell development?
- B cell precursors rearrange Ig genes
- Immature B cell bound to self Ag is removed
- Mature B cells bound to foreign antigen is activated
- activated B cells give rise to plasma and memory cells
where do BCR form?
In the bone marrow
where does B cell negative selection occur?
In the bone marrow
where do B cells go once they are activated?
mature B cells migrate to the periphery
where does antibody secretion and memory cells go?
in the bone marrow and lymphoid tissue
what B cell types can develop independent of antigen?
Stem cell
Pro B cell
pre B cells
what B cell types need antigen to develop?
immature B cell
mature B cell
germinal centre B cell
memory B cell
plasma cell
what is the germinal centre made up from?
mostly composed of proliferating B cells and ~10% antigen specfic T cells
how does the germinal centre change during infection?
It is dynamic
- grows as the immune response increases, shrinks and disappears when infection is cleared
what are the structure of a transverse section of white pulp?
-Germinal centre
- B-cell carcinoma
- Marginal zone
- Perifollicular zone
Central arteriole
periarteriolar lymphoid sheath
-red pulp
why does IgM form a pentameric structure?
More binding sites for antigen meaning antigen is more likely to bind and the signal to be sufficient to start an immune response as IgM is the initiat antibody produced
what is antibody class switching?
Cytokines can induce RNA transcript production in “switch regions” near the heavy chain segment they preferentially induce
when does a B cell start secreting IgM?
once it interacts with antigen
what is the function of the switch region of B cells that regulates antibody class?
Special switch region sequences cause formation of secondary DNA structures that promote pausing of RNA polymerase II and binding of activation induced cytidine deaminae (AID)
what is AID?
only produced on activated B cells
- can induce class switching of antibody
(AID can only bind ssDNA)
what does AID drive?
somatic hypermutation and class switch recombination
what are the regions of antibody?
- Antigen binding site
- Variable region
- Constant region
when does somatic hypermutation occur?
Occurs after antigen-driven B cell activation as part of the germinal centre response
what is somatic hypermutation?
Introduction of point mutations
- A 50% chance at each division that a B cell will acquire a mutation in antibody it encodes
what is the function of somatic hypermutation?
- Allows more diversity in the antibody region
- Some increase antigen binding strength
- Some decrease antigen binding strength
The higher binding antibody outcompetes the others
what is AID?
Activation induced cytidine deaminase (AID)
what is the role of AID in somatic hypermutation?
Deaminates DNA
- leads to base pair mismatches
- lesion repair induces mutations
- Doesn’t have the same sequences that stall RNA polymerase II as switch regions do
- Mechanism for RNA pol II stalling is unknown
where does somatic hypermutation occur?
Point mutations are induced into rearranged variable regions at a high rate
- occurs at “hotspots” in the genes
what is the role of 3’ enhancers in somatic hypermutation?
Enable chromosomal looping
- this forms transcriptional domains that control transcriptional levels enabling AID to bind
- Without the 3’ enhancers there is no somatic hypermutation, no class switch recombination
what are the important things that help somatic hypermutation?
RNA polymerase II pausing is necessary to allow AID to bind and introduce a lesion, and the 3’ enhances are critical to drive the high levels of transcription that start the process
