B-Lymphocyte Activation Flashcards
What initiates signal transduction in B lymphocytes?
Ag-mediated cross-linking of BCRs
What happens after Ag-mediated cross-linking of BCRs?
Phosphorylation of tyrosines in ITAMS of the Iga (alpha) and IgB (beta) chains -> NOT CD3 molecule as with T cells
What is the role of the tyrosines in Iga (alpha) and IgB (beta) when phosphorylated, what binds to them?
These phosphorylated tyrosines act as docking sites for other molecules such as:
- PTK Syk (protein tyrosine kinase)
- BLNK (SLP-65) (DIFFERENT TO T CELL, 76 in TCs)
What molecules are responsible for phosphorylation of tyrosines on Iga and IgB?
(3)
Src-family kinases such as Blk, Fyn or Lyn
What is the next step in cell signalling after phosphorylation of tyrosines on Iga and IgB by Src family kinases?
Syk binds to the doubly phosphorylated ITAMS and is activated upon binding
How does Syk bind to the ITAMS on both the alph and beta Ig?
Syk has two tandam SH2 domains which bind to phosphorylated tyrosines in ITAMS
What is BLNK, what is it also called?
(3)
B cell linker protein
Its an adaptor protein
Its also called SLP-65
What does activated Syk do?
It phosphorylates BLNK
What does BLNK do once phosphorylated?
Activated BLNK is joined by Btk and phospholipase Cy2 (PLCy2)
What happens after BLNK is joined by Btk and PLCy2?
Btk is phosphorylated by Syk
What does Btk do once phosphorylated?
It phosphorylated PLCy2, activating it
What does activation of PLCy2 result in?
Results in early calcium signalling and initiation of PKC-dependent pathways
Same pathway as in T cells -> PLCy2 will find PIP2 in membrane and hydrolyse it etc etc
What is the T cell equivalent of Btk?
Itk
What are the three signalling pathways of a B cell
PLCy2:
- IP3 –> Ca2+ -» NFAT
- DAG –> PKC -> NFkB
G protein -> GTP/GDP -> Ras -> ERK -> JNK -> AP-1
What happens in X linked agammaglobulinaemia?
Btk is mutated
Btk is involved in activating B cells -> without this there is no mature B cells and no antiodies etc
Mutations in what genes can cause agammaglobulianemia?
(3)
Iga or IgB
Btk
BLNK
What is the T cell equivalent of agammaglobulinaemia?
SCID
Severe combined immuno deficiency
Mutations in what genes can cause SCID
(4)
CD3y, CD3B, CD3a, CD3zeta
Lck
ZAP-70
CD45
What three proteins is the B cell co-receptor made of?
CD19
CR2
CD81
What is the role of CD19, CD2 and CD81 in B cell signalling?
(3)
CD19 is responsible for getting the signal into the cell -> cytoplasmic tail
CR2 -> recognises iC3b and C3d (complement derived fragments)
CD81 -> Transports CD19 cell surface i.e. it lowers the threshold for B cell receptor activation
How does complement result in B cell activation?
(6)
C3b is found on the pathogen surface
CR1 (C3b ligand) is found on B cells, binding facilitates C3b cleavage by factor I into iC3b and then into the more stable C3d
CR2 (part of BC co-receptor) can now bind C3d
BCR and BCCR are brought close together
Lyn found on Ig(alpha) phosphorylates the cytoplasmic tail of CD19 (of BCCR)
Cytoplasmic tail then binds intracellular signalling molecules to generate an activation signal resulting in changes in gene expression
What is C3b’s ligand and where is it found?
CR1 (C3b ligand) is found on B cells,
What does C3b binding to CR1 facilitate?
Facilitates C3b cleavage by factor I into iC3b
Cleaved further into more stable C3d
What does C3b binding to CR1 facilitate?
Facilitates C3b cleavage by factor I into iC3b
Cleaved further into more stable C3d
What binds C3d?
CR2 on the B cell
What happens when CR2 binds C3d?
The B cell receptor complex and B cell co-receptor are brought close together
What happens when the BCR and the BCCR come close together?
The Iga-bound tyrosine kinase (Lyn) phosphorylates the CD19 cytoplasmic tail
This then binds intracellular signalling molecules etc etc
What membrane-associated Src protein tyrosine kinases are used in T cells vs B cells?
p56 Lck and Fyn in T cells
Lyn, BLk and Fyn in B cells
What phosphorylates ITAMS in T cells vs B cells (for gene transccription)
ZAP-70 in T cells
Syk in B cells
What adaptor molecules are used in T cells versus B cells?
LAT and SLP-76 in T cells
BLNK (SLP-65) in B cells
What adaptor molecules are used in T cells versus B cells?
LAT and SLP-76 in T cells
BLNK (SLP-65) in B cells
