Case 16: Wiskott-Aldrich Syndrome

Question 1

what does the eukaryotic cell cytoskeleton consist of?

Answer 1

1. actin
2. microtubules
3. intermediate filaments

Question 2

what’s the purpose of the cell cytoskeleton?

Answer 2

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

Question 3

what is Wiskott-Aldrich syndrome?1

Answer 3

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

Question 4

what happens to the cytoskeleton of a T cell when it binds to a B cell?

Answer 4

1. 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
2. TH cell reorients its cytoskeleton and secretory apparatus towards the B cell
3. IL-4 is released into and is confined to the space between the B cell and TH cell

Question 5

why does the cytoskeleton respond to changes in the plasma membrane?

Answer 5

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

Question 6

how does the cytoskeleton play a role in T cell migration?

Answer 6

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

Question 7

what roles does the T cell cytoskeleton play?

Answer 7

1. secretion of cytokines
2. cell migration
3. cell division

Question 8

how is the cytoskeleton involved in cell division?

Answer 8

the actin cytoskeleton, which, along with myosin,

forms a contractile ring that divides the cell in two

Question 9

what mutation causes WAS?

Answer 9

C–>T change in the WAS gene resulting in a premature stop at codon 13

Question 10

whats the clinical presentation of WAS?

Answer 10

1. bloody diarrhea
2. eczema
3. thrombocytopenia with small platelets

Question 11

what’s the inheritance of WAS?

Answer 11

x-linked

Question 12

why do mutation sin WASP lead to WAS?

Answer 12

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

Question 13

what are the characteristics of WAS?

Answer 13

1. T cells and platelets are defective in number and function
2. T cell movement, capacity for cell
   division, capping of antigen receptors, and reorientation of the cytoskeleton on
   engagement with other cells are all impaired
3. function of monocytes,
   macrophages, and dendritic cells is also affected, with significant defects in
   directional motility and phagocytosis
4. cytotoxic function of natural killer cells
   (NK cells) is impaired
5. distinct abnormalities of B lymphocytes have also
   been described

Question 14

why are there small platelets in WAS?

Answer 14

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

Question 15

why type of infections are WAS patients more susceptible to?

Answer 15

1. pyogenic bacterial infections
2. opportunistic infections

maybe due to impaired cytotoxic function of CD8 T cells and NK cells in WAS = they can’t attach to target cells

Question 16

how do you treat WAS?

Answer 16

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

Question 17

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?

Answer 17

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

Question 18

Can you devise a strategy that might induce isotype switching in WAS B cells
to overcome the lack of T-cell–B-cell collaboration?

Answer 18

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

Question 19

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?

Answer 19

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