Case 16: Wiskott-Aldrich Syndrome Flashcards
what does the eukaryotic cell cytoskeleton consist of?
- actin
- microtubules
- intermediate filaments
what’s the purpose of the cell cytoskeleton?
it provides
a framework for the internal structural organization of the cell
also
essential for cell movement, cell division, and many other cell functions
many functions of T cells require the directed reorganization of the cell’s cytoskeleton,
in particular the actin cytoskeleton
what is Wiskott-Aldrich syndrome?1
the actin cytoskeleton is a dynamic structure and can undergo rapid reorganization by
the depolymerization and repolymerization of actin filaments
in WAS, the inability of T cells to reorganize their actin cytoskeleton when required has profound effects on their function and thus on immune function as a whole
without their cytoskeleton, they can’t interact with B cells, do cell division, or cell migration
what happens to the cytoskeleton of a T cell when it binds to a B cell?
- helper T cell adheres to MHCII:antigen complex on B cell and begins to synthesize IL-4 and CD40L which binds to CD40 on B cell
- TH cell reorients its cytoskeleton and secretory apparatus towards the B cell
- IL-4 is released into and is confined to the space between the B cell and TH cell
why does the cytoskeleton respond to changes in the plasma membrane?
the cytoskeleton is linked to cell-surface receptors in the plasma membrane
so that events occurring at the membrane can drive cytoskeleton reorganization
ex. cross-linking of T-cell antigen receptors and co-receptors by
antigen:MHC complexes leads to their aggregation at one pole of the T cell, with an
accompanying concentration of the actin cytoskeleton at that point.
actin cytoskeleton reorganizes to the zone of contact which in turn causes a microtubule-dependent
focusing of the secretory apparatus of the T cell on the point of contact with the B
cell
so the release of cytokines from the T cell is thus directed to the contact
point
how does the cytoskeleton play a role in T cell migration?
T cells move in a crawling ‘ameboid’ fashion and they do this via their cytoskeleton
they need their cytoskeleton to move from the thymus into the blood vessels and subsequently ‘home’ from
the bloodstream into lymphoid tissue
what roles does the T cell cytoskeleton play?
- secretion of cytokines
- cell migration
- cell division
how is the cytoskeleton involved in cell division?
the actin cytoskeleton, which, along with myosin,
forms a contractile ring that divides the cell in two
what mutation causes WAS?
C–>T change in the WAS gene resulting in a premature stop at codon 13
whats the clinical presentation of WAS?
- bloody diarrhea
- eczema
- thrombocytopenia with small platelets
what’s the inheritance of WAS?
x-linked
why do mutation sin WASP lead to WAS?
WASP = Wiskott-Aldrich syndrome protein
it has homology with actin-binding cytoskeletal proteins
involved in the reorganization of the actin cytoskeleton in white blood cells
and platelets
WASP is expressed only in white blood cells and megakaryocytes
this explains the restriction of its effects to
immune system and blood clotting functions
what are the characteristics of WAS?
- T cells and platelets are defective in number and function
- T cell movement, capacity for cell
division, capping of antigen receptors, and reorientation of the cytoskeleton on
engagement with other cells are all impaired - function of monocytes,
macrophages, and dendritic cells is also affected, with significant defects in
directional motility and phagocytosis - cytotoxic function of natural killer cells
(NK cells) is impaired - distinct abnormalities of B lymphocytes have also
been described
why are there small platelets in WAS?
platelets in the circulation
become spontaneously activated and they extrude their granules
for this
reason they appear small and their volume and diameter are smaller than normal
why type of infections are WAS patients more susceptible to?
- pyogenic bacterial infections
- opportunistic infections
maybe due to impaired cytotoxic function of CD8 T cells and NK cells in WAS = they can’t attach to target cells
how do you treat WAS?
BM transplant
although regular administration of immunoglobulins,
antibiotic prophylaxis, and measures to avoid severe trauma-related bleeding
are all important components of the treatment plan, severe manifestations and a failure to express WASP are an indication for hematopoietic cell transplantation
When Mrs Stilton and other female heterozygous carriers of WAS are
examined for randomness of X-chromosome inactivation, nonrandom inactivation
of the WAS-bearing X chromosome is found in all the blood cell lineages—
monocytes, eosinophils, basophils, neutrophils, B lymphocytes, and CD4 and
CD8 T lymphocytes. When hematopoietic stem cells are isolated from these
women, they also exhibit nonrandom X inactivation. How might this be explained?
signals that direct the maturation of hematopoietic stem cells into the various lineages
are transmitted by their contact with stromal cells in the bone marrow
presumably,
this interaction, like T-cell–B-cell interaction, requires cytoskeletal reorientation,
and thus will be impaired in cells containing an active affected X chromosome.
the stem cells bearing an active normal X chromosome thus have a survival advantage
an alternative hypothesis, based on studies in mice, is that fetal liver hematopoietic
stem cells that express WASP have a significant advantage over WASP-negative cells
in reaching the bone marrow
Can you devise a strategy that might induce isotype switching in WAS B cells
to overcome the lack of T-cell–B-cell collaboration?
You might try to give antibody against the B-cell cell-surface protein CD40 along with
the immunogen
ligation of CD40 by the CD40 ligand borne by activated T cells is
a signal for a resting B cell to start dividing and to undergo isotype switching
the
antibody should act like the CD40 ligand and induce isotype switching in B cells
Males with XLT are often initially given a diagnosis of chronic idiopathic
thromobocytopenia purpura. Can you think of any laboratory test that would make
you suspect XLT?
Measurement of mean platelet volume (MPV) may help diagnose XLT
WAS and XLT
are the only conditions that are typically associated with low MPV. In contrast, the
MPV is normal or even elevated in patients with chronic ITP
