Examples of immunodeficiencies
affecting T-cells are listed here.
So for example, a defective gene for the
CD40 ligand, or for CD40 itself, or for
AID or for NEMO or for UNG, result in a
condition called hyper-IgM syndrome.
And you can read through
this list for yourself.
You can see a number of different gene defects
causing a number of different consequences.
In hyper-IgM syndrome, there
is raised serum IgM and IgD.
You’re probably thinking, hang on a minute, I
thought we were talking about immunodeficiency?
And yet you’re telling me that there is
raised serum IgM and IgD, that there’s more.
Hyper-IgM it sounds good doesn’t it?
You got more IgM than other people.
But the problem is, that there is
very low or absent IgG, IgA and IgE.
Most patients have an X-linked form of the hyper-IgM syndrome,
in which there is a defect in the gene encoding CD40 ligand.
Less commonly, there is a defect in
the gene encoding a molecule called
NEMO, which is the NF𝜅B essential
modifier, sometimes known as IKKγ.
And in some patients there is a defect in the gene
encoding CD40, which is an autosomal gene or in the gene
encoding the activation-induced cytidine deaminase (AID)
or in the gene encoding uracil-DNA glycosylase (UNG).
The result is recurrent
There is also a condition called Hyper-lgE
Syndrome and in this condition there is immune
dysregulation with an increase in the level of lgE
antibody as the name suggests Hyper-lgE Syndrome.
An increase in the number of
eosinophils, B-cells and natural killer
cells but a decrease in CD8+ T-cell
proliferation and activation.
There are autosomal dominant mutations in STAT3 or
autosomal recessive mutations in TYK2 or DOCK8.
STAT3 and TYK2 are involved in signaling
through several different cytokine receptors.
DOCK8 deficiency results in an
effect on the actin cytoskeleton.
As we can see here, from signaling through
a pattern recognition receptor, being
delivered through MyD88, DOCK8 is involved
in actin cytoskeleton rearrangement.
DiGeorge Syndrome results from
mutations in the TBX1 transcription
factor which is involved in embryonic development.
There is a failure of the thymus to
develop and of course the thymus is
where T-cells develop and you need a
thymus in order for T-cells to develop.
So there's a defect in helper T-cells, in
regulatory T-cells and in cytotoxic T-cells.
And cell-mediated immune
responses are undetectable.
Antibody responses are also poor due to a lack of
T-cell help for antibody production from B-cells.
However, actually a complete absence
of the thymus is relatively rare.
And more commonly the situation is
a partial DiGeorge syndrome where
there are still some T-cells, so the
thymus doesn’t fully develop but
it develops enough to produce some
T-cells or be it at a reduced level.
Treatment can be by
grafting neonatal thymus.
In Wiskott-Aldrich syndrome, there is
a defective Wiskott-Aldrich syndrome
protein (WASp) due to a defect in
the gene that encodes that protein.
There is compromised T-cell motility, phagocyte
chemotaxis, dendritic ccell trafficking and the
polarization of the T-cell cytoskeleton towards
B-cells during T-cell-B-cell collaboration.
In the early phases of T-cell activation, the adhesion
molecules are scattered randomly across the surface.
However with activation of WASP by
ZAP-70 there is induction of the
actin cytoskeleton to form what is
called an immunological synapse.
This is essentially the T-cell receptor interacting
with peptide MHC plus the CD4 or CD8 molecule
and all the other associated adhesion molecules
that are required for optimal stimulation.
They all group together in the same area on the surface of
the T-cell producing this so called immunological synapse.
In MHC Class I deficiency you will not be surprised
to hear there is a deficiency of MHC Class I.
In order for MHC Class I to get to the surface of a cell it
has to have a peptide sitting in its peptide binding groove.
Without a peptide, there is no transport
of MHC Class I to the cell surface.
And MHC Class I deficiency can be caused by
mutations in the genes for TAP1, or TAP2 or Tapasin.
And each of these three molecules is required
for peptide loading into the MHC Class I groove.
So there will be no transport out of the
endoplasmic reticulum and no MHC Class
I on the cell surface so there will be
nothing for cytotoxic T-cells to see.
In MHC Class II deficiency, there are mutations
affecting the Class II transactivator
(CIITA) and this affects transcription factors
controlling class II gene expression.
Low expression of MHC Class II molecules on thymic
epithelium impairs the positive selection of CD4+ T-cells.
You'll recall that within the thymus there
are these thymic education events
that initially have positive selection
followed by negative selection.
And in the positive selection step,
T-cells that are developing
within the thymus initially, the double negative T-cells the
lack of expression of CD4 and CD8 they switch on expression of
these two genes to become double positive, CD4+, CD8+ T-cells.
And then there needs to be positive selection of
CD4+ T-cells to make sure that their T-cell receptor
is able to recognize peptides presented by your own
versions of MHC Class II, in other words self MHC.
And if that recognition doesn’t take place, then apoptosis,
programmed cell death occurs in the developing T-cells.
So they need to be
rescued from apoptosis.
And interaction with MHC Class II on the
thymic epithelial cells is what rescues them.
And of course if there’s no MHC Class II
there due to a deficiency of MHC Class
II, this rescue cannot take place and
therefore the CD4+ T-cells will not develop.
Recurrent bronchopulmonary infections
and chronic diarrhea occur within
the first year of life in individuals
with MHC Class II deficiency.
And death from overwhelming viral infections at
around about four years of age will happen unless
the patients are given appropriate treatment, for
example with a hematopoietic stem cell transplant.