B-cells initially start off
making the IgM class of antibody.
But following antigen stimulation, they will switch
to making other classes of antibody - IgG, IgA or IgE.
This class switching also takes
place at the genetic level.
Here we can see the immunoglobulin heavy chain gene
locus with the VDJ segment already recombined.
This is lying immediately upstream
of C mu (Cµ) and C delta (Cδ).
So the IgM class of
antibody will be produced.
However, following antigen stimulation, the antibody going
to be produced will be, in this instance, an IgE antibody.
This requires signals from helper
T-cells, for example CD40 ligand on the
surface of the T-cell interacting with
CD40 on the surface of the B-cell.
And also cytokines produced
by the helper T-cells.
What will happen in this particular case is that
the switch sequence immediately upstream of the Cµ
gene is going to be placed next to the switch sequence
immediately upstream of the C epsilon (Cε) gene.
So there’s a recombination of the
switch sequence for mu with the switch
sequence for epsilon, and the deletion of
the intervening constant region genes.
Now there will be transcription and RNA
splicing, and the messenger RNA encoding
the IgE antibody, in other words, VDJ
plus Cε will be translated into protein.
And plasma cells will secret
the IgE class of antibody.
Naïve B-cells co-express IgM
and IgD on their cell surface.
And when activated, and when they differentiate into
plasma cells, those plasma cells also secrete IgM and IgD.
Although they produce much,
much more IgM than they do IgD.
You’ll hardly be surprised to learn that yet again, it is
at the genetic level that this co-expression is determined.
Here we can see the already recombined VDJ segment
in the B-cell immunoglobulin heavy chain DNA.
And immediately downstream of this
recombined VDJ, is the Cµ and Cδ genes.
It’s very noteworthy that out of the nine Constant region gene
segments, all of them contain a switch sequence apart from Cδ.
And this permits the transcription of both
Cµ and Cδ genes together with the VDJ.
This enables the co-expression of IgM and IgD, which
we can see here on the surface of a naïve B-cell.
The primary RNA transcript containing both the Cµ and Cδ
genes is then alternatively spliced to produce messenger RNA
encoding Cµ, in other words an IgM antibody; or alternatively
spliced to contain Cδ which will encode the IgD antibody.
Here we have the typical B-cell receptor comprising
a transmembrane version of the antibody molecule.
You can see the typical antibody molecule here, with two
identical heavy chains, disulphide bonded to each other.
And two identical light chains, each of which
is disulphide bonded to one of the heavy chains.
The antibody molecule sits in the membrane of the
B-lymphocyte, held there by a transmembrane sequence.
Associated with the transmembrane
version of the antibody molecule
are two molecules called Ig-alpha (Ig-α) and Ig-beta (Ig-β).
Importantly, in the cytoplasmic domain of these two molecules,
there are ITAMs (Immunoreceptor
Tyrosine-Based Activation Motifs).
These are required for the B-cell to signal
into the nucleus once antigen is detected.
This is initiated by Src family kinases, adding
phosphates to the tyrosine residues within the ITAMs.
If we look at the different types
of B-cell that exists, there are
essentially two fundamentally different types of B-lymphocyte.
They’re called B1 and B2.
B1 cells are produced in the liver,
particularly in the fetus, and they are
self renewing cells, in other words
B1 cells will produce more B1 cells.
They are present in the
peritoneal and pleural cavities.
And they do not require T-cells
in order to become activated,
in other words they mediate
what we call a T-independent response.
The antibodies they produce are
low affinity IgM class antibodies.
And they’re often referred
to as natural antibodies.
And this term relates to the fact that the antibodies seem to
be produced in the absence of any obvious antigenic stimulation.
However, the majority of
B-cells are the B2 cells.
And in fact, whenever you hear anybody talking about B-cells or
B-lymphocytes, these are the cell type that they’re talking about.
B2 cells rather than B1 cells.
The B2 cells, as I’ve already mentioned
are the conventional B-cells.
They are replenished from the bone marrow, in other words the
bone marrow keeps producing more B-cells as they’re required.
They are present predominantly within the secondary lymphoid
tissues, although you can find them throughout the body.
And they require T-cells in order to
develop into plasma cells, and particularly
for class switching, to produce the
IgG, IgA and IgE classes of antibody.
And they can produce high affinity
antibodies of these three classes.