B cells and how they get activated Flashcards
where do B cells develop?
in the bone marrow
how do B cells get activated?
Mature B cells get activated in the spleen or lymph nodes by naked antigen through the B cell receptor
what is naked antigen?
antigen that is not presented by MHC
where are mature B cell found?
circulating through the body
what can B cells do?
- secrete antibody
- can present antigen on MHCII to CD4 T cells
- Can “class switch”
- Can undergo “somatic hypermutation”
- Undergo clonal expansion
- Can differentiate into antobody producing plasma cells
what is the initiat step in B cell activation?
By signalling through the B cell receptor
what is the B cell receptor?
Antibody bound to the plasma membrane
why is it important to know how and why B cells are activated?
- develop new cures for cancer: B cell malignancies (lymphoma and leukemia)
- Develop new treatments for autoimmune diseases
- Make new vaccines
how are B cell activated through the BCR?
Activation of a cell surface receptor through ligand binding doesn’t always directly link to the cell’s response
how does the activated BCR act?
The activated receptors can interact with a chain of other proteins within the cell that transmit the activation signal (signal transduction pathway)
what are kinases?
enzymes that phosphorylate themselves and other proteins- phosphorylation can generate binding sites for other proteins to allow the signal to transmit along the chain
what is the cellular messengering of BCR?
First messenger- antigen
Transmembrane B cell receptor (surface-bound immunoglobulin + Igalpha and Igbeta)
second messengers
Cascade
Functions
what is the structure of a BCR?
Cell surface immunoglobulin + one each of invariant signalling proteins Igalpha and Igbeta
- disulfide-link to form a heterodimer between Igalpha and Igbeta
what are the co-receptors of B cells?
CD21 and CD19
what is the role of B cell co-receptors?
Decreases BCR signaling threshold by amplifying BCR signals
Allows B cells to respond to low levels of antigen
what is CD21?
complement receptor 2- binds to the complement-coupled antigen
- antigen coupled to complement fragment
what is CD19?
augments signalling through BCR + recruites PI3-Kinase (growth signal)
what is the role of CD81?
trafficks CD19 to the cell surface
how are BCR presented on the cell surface?
there are many BCRs on the surface of one cell and they can move around the membrane on lipid rafts
what is BCR receptor clustering?
the BCR are on lipid rafts. This allows them to move around the cell membrane and means the signal can agrigate to one region of the BCR to get a much stronger response.
what can cause aggregation of BCR?
highly repetitive structures can cause aggregration of BCR on the cells surface
what is the role of T cells in B cell activation?
Needs T cells to help (cytokines and CD40L) to activate B cells
what is the BCR triggered?
Monovalent soluble antigen can cause the Src family kinase Lyn to ‘disturb’ and open the BCR allowing signal transduction
how does compliement act in BCR activation?
antigen bound to complimemt enhances the activation ability
how does antigen bind to a BCR?
Antigen bound complement fragments C3d or C3b can bond to CD21, the antigen binds to the antibody resulting in cross-linking
what is the intracellular signaling pathway in T cell activation?
-Tyrosine phosphorylation is an important mechanism by which transmembrane receptors transduce signals
- Phosphotyrosine residues are recognised by proteins containing the phospho-dependent binding domain, SH2
- SH2 domain proteins can act to recruit other molecules, as enzymes or as trancription factors
what are ITIMs and ITAMs?
Phosphorylation sites in immune receptors
what are ITIMs?
Immunoreceptor tyrosine-based inhibitory motifs
what are ITAMs?
Immunoreceptor tyrosine-based activation motif
what are Src family kinases?
Protein tyrosine kinases Fyn, Blk and Lyn associate with resting receptors
After ligand binding and receptor clustering the kinases phosphorylate tyrosines in ITAMs on Igalpha and Igbeta
what are the features of Syk kinase?
Syk has 2 SH2 domains and binds to pITAMs on Igbeta
Syk becomes activated by binding ti the phosphorylated site
what does syk activation induce?
formation of a membrane-associeated signalling complex
what is BLNK?
a scaffold protein
what is the structure of BLNK?
has multiple sites for tyrosine phosphorylation
what phosphorylates BLNK?
Syk
what is the role of BLNK once it is phosphorylated?
pBLNK recruits other Sh-2 domain proteins to form the multiprotein signalling complex
what is Bruton’s tyrosine kinase?
a protein that comes into the complex once BLNK is phosphorylated by Syk
what activates the PLCg2 pathway?
Bruton’s tyrosine kinase
what is the end result of the PLCg2 pathway?
upregulation of transcription factors
what does activation of transcription factors lead to?
- increased B cell maturation
- increased activation
what does activation of the PI3K pathway require?
Phosphorylation of CD19 (B cell co-receptor) by LYN
what does PI3K pathway activation lead to?
Leads to PIP3 production
This recruits BCR signalling components to the plasma membrane and activates them
what is the main mediator of the PI3K pathway?
Serine/ threonine kinase AKT is the main mediator of the PI3K pathway
what does the PI3K pathway regulate?
Cell cylce
Apoptosis
what is the role of AKT in the PI3K pathway?
AKT induces pro-survival genes through IKK and mTOR
what is mTOR?
kinase that controls cell growth and proliferation
what is the role of the PI3K pathway?
-promotes growth
-promotes survival
what activates the ERK pathway?
RAS activation
what is ERK?
a MAPkinase
how is ERK activated?
it is phosphorylated due to activated of RAS and this causes it to form a dimer
Dimerization allows translocation to the nucleus
what is the role of ERK in the nucleus?
-proliferation
-Survival
-Differentiation
how is ERK activated?
it is phosphorylated due to activated of RAS and this causes it to form a dimer
Dimerization allows translocation to the nucleus
