Humoral immunity - B cell activation Flashcards
What is the lymphocyte lineage?
- HSC will differentiate into either common myeloid or common lymphoid progenitor
- Common lymphoid will differentiate into either Pre-B or pre-T
- Pre-B will undergo Ig gene rearrangement and become an immature B-cell
What are the main phases of the humoral immune response?
- B cell makes IgM and IgD and expresses them on its surface
- Antigen activates B cell
- Th cell and other stimuli start the process of clonal expansion
- They can either make plasma cells -> produce Abs
- Some will express IgG (isotype switching - keep same specificity)
- Get affinity maturation - IgG can get higher affinity binding
- Also get memory B cells produced
How does Ig expression change during B cell maturation?
- Stem cell has no Ig
- Pre-B cell has cytoplasmic mu heavy chain and pre-B receptor
- As they become immature B cell, functional Ig is expressed as membrane IgM - acts as a BCR
- Once mature B cell, they get IgD
- When the B cell is activated by Ag and co-stimulated by T cell, you start getting low rate secretion of Ig, heavy chain isotype switching and affinity maturation
- Finally you have an Ab secreting cell, with high rate of Ig secretion and reduced membrane bound Ig
What are the 3 signals B cells need to be activated?
- Antigen binding to B-cell receptor (sIgM), resulting in stimulation of signal transduction pathways
- Co-stimulation by T-cell - have to agree that there is a foreign ag that needs dealing with
- Co-stimulation by cytokines
What happens when an ag binds to the BCR?
- Proteins associated with BCR
- One is a protein TK binding of Ag causes activation of TK
- Activates signal transduction pathways for cell division and differentiation -sends growth signals
- The major receptors for growth stimulation are TK receptors such as EGF, insulin receptor and FGF
What are the 2 forms of Abs?
- Membrane-bound on B cell surface - Ag receptor
- Secreted (circulation, tissues, mucosa)
How does the activated B-cell start to secrete soluble IgM?
- Differential splicing
- The constant region of IgM is actually coded for by 4 different exons, with two alternative versions of exon 4
- Differential splicing gives 2 different mRNAs, coding for 2 proteins that differ at the C terminal end
- The V region, coded for by VDJ complex, is identical
- These different mRNAs give either secretory or membrane bound IgM
Where are membrane and secreted forms of IgG made?
Membrane
- Made in the RER, modified in the golgi, go to the membrane
- Cytoplasmic tail of hydrophobic proteins anchors it into the membrane
Secretory
- Made in RER and processed in golgi, taken in vesicles to cell surface.
- When it reaches the membrane, it doesnt become embedded, it is secreted as it doesnt have the cytoplasmic tail
What are the 3 main functions of sIg?
- Neutralisation of microbes and toxins
- Opsonisation of microbes to enhance phagocytosis
- Activation of complement
Why do we have class-switching?
Different Ig classes work best at certain sites (IgM IgG - blood; IgA - mucosa) or work best against certain pathogens (IgE - parasites)
What is class switching?
- During an immune response B cells can produce Igs of different classes, without changing specificity.
- IgM -> IgG, A or E
- IgG -> IgA or E
What are the two mechanisms for class switching?
Minor
- IgD only by differential splicing, made at the same time as IgM
Major
- all other classes, by DNA arrangement
What is the process of minor class switching?
- C mu and C delta are transcribed as part of a single precursor of RNA
- Differential splicing can remove the C mu exons, so just the C delta exons are used
- Results in same VDJ, but joined to C delta - now making IgD
What is the process of class switching by further DNA rearrangement (Major)?
- Have VDJ complex before the C exons coding for any other Ig class
- Enzyme recombinase can cut at different places in the DNA and carry out somatic rearrangement
- This can give the VDJ transcribed next to a different C region of a different class
- Cannot revert back the enzyme gets rid of the DNA it cuts out
How do T cells help class switching?
- CD40L on T cell interacts with CD40 on B cells
- Cytokines produced by T cell:
. IFN-gamma -> switch to IgG1, IgG3
.IL-4 -> switch to IgE
. TGF-beta -> switch to IgA
