B cell activation and signaling Flashcards
What are SCSMs, what do they do, where are they located?
SCSM = subcapsular sinus macrophages
functions:
- can’t phagocytose
- don’t process Ag
- display Ag on surface
located in follicles in LNs
What are FRCCs, what do they do, where are they located?
FRCC = follicular reticular cell conduits
function: present Ag on surface
present in LN
Describe the delivery of Ag to B cells
- opsonized Ag enter afferent lymphatics
- SCSM bind with Ag with complement Rs and transport it into the follicle
- non-Ag specific B cell grabs Ag with complement R or FcR
- FDC grabs Ag with complement Rs
- Ag-specific B cell recognizes Ag with BCR
What are the signaling subunits of the BCR, what domains do they have>
IgAlpha and Igbeta, both contain ITAMs
Describe the B cell surface when it is unstimulated
- ITAMS in IgAlpha and IgBeta are not phosphorylated
- Src kinases (e.g. lyn) are not activated and are physically seperated from the BCR in lipid rafts
Describe BCR signaling cascade
- Ag induce BCR conformational change that moves BCR into lipid rafts
- IgAlpha and beta chains are brought into close proximity to Lyn in lipid rafts
- Lyn is activated by dephosphorylation, activated Lyn phosphorylates the ITAMs
- Syk binds ITAMs via SH2 domains and is recruited to the membrane
- Syk is activated by phosphorylation of Lyn
- BLNK recognizes P-tyr on IgAlpha/beta
- Syk phosphorylates BLNK
- PLCg is attracted to P-BLNK and is brought into close proximity to its substrate PIP2
- BTK is attracted to P-BLNK and is brought into close proximity to its substrate PLCg
- BTK is phosphorylated by Lyn
- Btk phosphorylates PLCg and enhances its enzymatic acitvity
Describe some characteristics of Syk: structure, where it’s expressed, subcellular location, critical functions
- structure = two SH2 domains + tyr kinase
- expressed = primarily in B cells
- subcellular location = found in the cytoplasm of non-activated cells
- critical functions = critical for BCR signaling
Describe the three concertic rings in the B cell immunological synapse
- Ag-BCR complexes in the center
- adhesion molecules, e.g. LFA-1
- polymerized actin (outer)
What kind of protein is BLNK? Describe its strcuture
adaptor protein
- SH2 domain that binds to P-IgAlpha
- SH3
- sites with tyr that when phosphorylated are recognized by SH2 domain-containing proteins
What additional signals regulate BCR signaling?
- other signals B cells receive through B cell surface Rs can influence BCR signaling
- some signals function in a +ve way and enhance BCR signaling
- some signals antagonize BCR signaling and are a way of turning off or limiting the magnitude of BCR signaling
What is the B cell co-R complex, when is it expressed?
- multi component R
- co-R is expressed early in B cell development and is present on mature and memory B cells
What are the different components in the B cell co-R complex, what does each one do?
- CD21 (complement R 2)
- binds C3d complement - CD19
- signaling subunit
- recruits SH2 domain-containing signaling proteins to phosphorylated tyrs in its intracellular tail - CD81 (TAPA-1)
- complexes with integrins and provides more activation signaling
Describe B cell co-R complex signaling
- simulatenous engagement of BCR and co-R complex with Ag+C3d brings BCR-associated kinases in close proximity to CD19 intracellular tail
- phosphorylation of CD19 recruits SH2 domain-containing signaling proteins (e.g. P13K, a lipid kinase)
- amplifies BCR signaling
What did studies measuring B cell signaling find when only anti-IgM Ab was used vs anti-IgM Ab + anti-CD19 Ab?
takes less Ag to stimulate a response in the anti-IgM Ab + anti-CD19 group
What did the study of C3d of complement as a molecular adjuvant find?
When Ag was conjugated to C3d there was a greater immune response, even more so when there were mutliple C3ds conjugated to the Ag
