WiskottAldrich Syndrome, Leukocyte Adhesion Deficiency, and Other

Migration Defects in Human Primary Immunodeficiency

Dale A Moulding and Adrian J Thrasher, UCL Institute of Child Health, London, UK
2016 Elsevier Ltd. All rights reserved.

Glossary
Chemotaxis Directional migration toward a biochemical Microthrombocytopenia Platelets are unusually small and
stimulus. present in lower than normal numbers.
Hypogammaglobulinemia Deciency of all types of Myelokathexis Neutrophil retention in the bone marrow.
immunoglobulins.

Abstract

Migration is essential for immune system function, from the establishment of the hematopoietic system in the bone
marrow through to the capture and killing of invading pathogens. This reliance on migration is demonstrated by the existence
of a subset of inherited immunodeciencies that are a result of mutations that impact on migratory processes. Much of our
understanding of the importance of migration in the immune response comes from the study of these immunodeciencies.
WiskottAldrich syndrome is the rst described and best studied migratory immunodeciency, and this article will focus on
this disorder, and its wide ranging impact on immune function. We will also give an overview of other migration defects that
lead to immunodeciency, including their genetic, biochemical, and cell biological basis.

Introduction
The immune system serves to protect the host from invading
pathogens and malignancies by the recognition of foreign mole-
cules (antigens) that are not naturally present in the host.
Immune cells then act to destroy these pathogens, infected or
malignant host cells expressing the antigenic molecules. This is
achieved by constant surveillance of the host for the presence
of antigens, through the passive migration of immune cells in
circulating blood and lymph systems, and active migration
through tissues and organs (Forster and Sozzani, 2013). Migra-
tion is key to the success of the immune system, not just in being
able to nd antigens, but also at almost every stage of an
immune response. This dependence on migration is exemplied
by the primary immune deciency (PID) known as Wiskott
Aldrich syndrome (WAS). Additionally, a variety of other migra-
tory immunodeciencies exist, further highlighting the impor-
tance of migration in the immune response. The study of these
PIDs has helped reveal the numerous migratory steps involved
in a successful immune response, and the molecular and cellular
processes that are involved. These include the ability to attach to
blood vessels in order to migrate into tissues, defective signaling
from cell surface receptors, and problems with controlling the
cytoskeleton to change cell shape and generate the force neces-
sary for directed migration.
WiskottAldrich Syndrome
Symptoms, Discovery, and Genetics
WAS is characterized by a classical triad of symptoms: recurrent
bacterial infections, eczema, and microthrombocytopenia
(see Table 1 for clinical signs and treatment options). The
condition was rst described in 1937 by Dr Alfred Wiskott
(Wiskott, 1937), and again in 1954 by Dr Robert Anderson
Aldrich (Aldrich et al., 1954), and has been well documented
in many recent reviews (Moulding et al., 2013; Bouma et al.,
2009; Thrasher and Burns, 2010; Massaad et al., 2013). The
initial description by Alfred Wiskott was for three brothers,
and Robert Aldrich subsequently described the condition
only affecting males from six generations of a single family,
strongly suggesting an X-linked inheritance. This X-linked
inheritance was conrmed in 1994 when the gene responsible
was identied, located on the X-chromosome (Derry et al.,
1994). The WAS gene encodes for a 502 amino acid protein
that plays an important role in the control of the actin cytoskel-
eton. There are over 300 disease-causing mutations described
in the WAS gene (Massaad et al., 2013; Jin et al., 2004; Ochs
and Thrasher, 2006; Albert et al., 2010), that give rise to three
distinct conditions: the disease for which the gene is named,
WAS; a milder form of the disease called X-linked thrombocy-
topenia (XLT); and a disease with a surprisingly different
molecular basis called X-linked neutropenia (XLN).
Actin Cytoskeletal Restructuring by WASp
The actin cytoskeleton is the driving force behind cellular
migration (Salbreux et al., 2012; Pollard and Cooper, 2009),
so the dysfunctional control of the cytoskeleton in WAS
patients leaves immune cells unable to migrate efciently.
WiskottAldrich syndrome protein (WASp) is the founding
member of a family of proteins that control the formation
of branched (dendritic) actin laments through control of
a catalytic complex of proteins termed the ARP2/3 complex

416 Encyclopedia of Immunobiology, Volume 5 http://dx.doi.org/10.1016/B978-0-12-374279-7.18010-5

 Immune Deficiency j WiskottAldrich Syndrome, Leukocyte Adhesion Deficiency, and Other Migration Defects 417

Table 1 Clinical signs and treatment options for migratory immunodeciencies

Disease Clinical signs Therapeutic options References

WiskottAldrich syndrome (WAS)
(and WAS Interacting Protein
(WIP) deciency)
X-linked neutropenia
Dock8 deciency
Coronin 1A mutation
Rac2 neutrophil immunodeciency
syndrome
RhoH mutation in
epidermodysplasia verruciformis
Neutrophil actin dysfunction
syndrome
Warts, hypogammaglobulinemia,
infections and myelokathexis
syndrome
Leukocyte adhesion deciency
Eczema, thrombocytopenia, prone
to recurrent bacterial, fungal, and
viral infections, bloody diarrhea,
increased tendency to bleed
leading to petechiae or bruising
Recurrent bacterial infections,
neutropenia, monocytopenia,
possible myelodysplasia
Severe food or environmental
allergies, otitis media,
pneumonia or bronchitis,
Staphylococcal skin infections,
eczema, eosinophilia, IgE
dysregulation, and severe
cutaneous viral infections
EBV-induced B cell
lymphoproliferative syndrome,
recurrent bacterial and fungal
infections, particularly ear, nose,
and throat. T cell lymphopenia
Severe recurrent bacterial
infections, poor wound healing
Disseminated at warts with HPV3,
at red or red-brownish plaques,
and depigmented pityriasis
versicolor-like lesions with HPV 4
Severe recurrent bacterial infection.
Neutrophil phagocytosis and
chemotaxis defective
Recurrent bacterial infections,
susceptibility to HPV and
development of warts
Recurrent bacterial infections,
neutrophilia
(for classical severe WAS)
Prophylactic immunoglobulin and
antibiotics. Denitive treatment
with hematopoietic stem cell
transplant (HSCT) or possibly
gene therapy (under evaluation)
G-CSF therapy and prophylactic
antibiotics according to clinical
severity
Prophylactic immunoglobulin,
antibiotics, and antiviral agents.
Denitive therapy HSCT
Denitive therapy HSCT
Prophylactic antibiotics and
antifungal agents. Denitive
therapy HSCT
Topical antiviral agents, laser
therapy. Possible denitive
therapy HSCT, but may be
residual keratinocyte defects
Denitive therapy HSCT
Topical antiviral agents, laser
therapy. Prophylactic
immunoglobulin infusions,
G-CSF and GM-CSF injections.
CXCR4 antagonist therapy in trial
Denitive therapy HSCT
Ochs et al. (2009), Aiuti et al.
(2013), and Hacein-Bey Abina
et al. (2015)
Devriendt et al. (2001), Ancliff
(2003), Ancliff et al. (2006), and
Beel et al. (2009)
Engelhardt et al. (2009) and Zhang
et al. (2009), Su, 2010, Chu et al.
(2012), and Aydin et al. (2015)
Moshous et al. (2013), Punwani
et al. (2015)
Ambruso et al. (2000)
Crequer et al. (2012) and Jablonska
et al. (1979)
Camitta et al. (1977) and Coates
et al. (1991)
Wetzler et al. (1990) and
McDermott et al. (2011)
Elhasid and Rowe (2010)

(a) (b)
(Welch et al., 1997; Mullins et al., 1998; Goley and Welch, EVH1 B GBD Branched actin network
PPP

n
tio
er in
iza

2006). WASp has no intrinsic catalytic activity, but serves as VCA

lym Act

Podosomes
a scaffold and activator for the ARP2/3 complex. Through inte-
po

gration of a wide variety of signals, WASp activates the ARP2/3 WASp activation
ARP2/3
complex to direct polymerization of new, branched actin la-
A

ments (Figure 1). This activation is subject to tight temporal

VC

Cdc42
and spatial regulation, meaning that the actin cytoskeleton is
P
PP

modied in strictly dened regions of the cell, allowing for
the highly localized restructuring needed for processes such
as migration and phagocytosis.
WASp is one of the family of eight proteins that control the
ARP2/3 complex, but is the only ARP2/3 activator whose
expression is restricted to the immune system (Derry et al.,
1994). The other members of the WASp family are more widely
expressed in multiple cell lineages (Suetsugu et al., 1999; Miki
et al., 1996; Campellone et al., 2008; Zuchero et al., 2009;
Linardopoulou et al., 2007). All WASp family proteins perform
the same function: they integrate signals to control activation of
the ARP2/3 complex. It is signicant that the immune system
EVH1 B GBD
Migration
Figure 1 WiskottAldrich syndrome protein (WASp) activation and
function during immune cell migration. (a) WASp domain structure
showing the inactive form with the VCA domain sequestered by the
GTPase-binding domain. Activation by GTP-bound Cdc42 (and other
activating molecules see main text) releases the VCA domain allowing
binding and activation of the ARP2/3 complex. This in turn catalyzes
the polymerization of a new branch of F-actin from a preexisting actin
ber. (b) WASp is required to produce podosomes and the dendritic
branched actin network in the lamellipodia of migrating cells.
Podosomes provide adhesion and traction, while the growing dendritic
actin network provides force. Together they drive migration.
418 Immune Deficiency j WiskottAldrich Syndrome, Leukocyte Adhesion Deficiency, and Other Migration Defects
has evolved to express a unique ARP2/3 regulator, further indi-
cation of the importance of cytoskeletal restructuring and
migration in these cells.
WASp activity is regulated by signaling from the cell
surface in response to a wide variety of stimuli, including che-
moattractants, integrin binding, cytokines, direct cellcell
interactions, and even the local curvature of the cell
membrane (Padrick et al., 2008; Gallop et al., 2013). WASp
is a multidomain protein containing ve distinct domains:
the N-terminal EVH1 domain, the basic domain, the GTPase
binding domain (GBD), the polyproline domain, and the
VCA domain located at the C-terminal (Blundell et al.,
2010). Before activation, WASp exists in the cytosol in an
autoinhibited conformation, with the VCA domain tethered
to the central GBD domain (Figure 1). Activation is mediated
by binding of GTP-bound Cdc42 to the GBD domain, phos-
phorylation of Tyr291 also in the GBD, and binding of phos-
phatidylinositol 4,5-bisphosphate to the basic domain.
Additionally, there is an association with an expanding list
of kinases, adapter proteins, and actin-binding proteins that
associate with the polyproline domain (Campellone and
Welch, 2010; Thrasher and Burns, 2010; Blundell et al.,
2010). Optimal activation of WASp may require coordinated
input from a variety of these activators, with this multilevel
regulation of WASp, potentially allowing for ne-tuning of
its activation status. Following activation, the VCA domain
is released from its inhibitory association with the GBD and
can bind to and activate the ARP2/3 complex, which in turn
catalyzes the formation of branched actin laments
(Figure 1).
The loss of WASp function is the underlying cause of all the
cellular and immunological defects in WAS and XLT. In WAS,
this loss of activity tends to be more severe than in XLT, due to
mutations that lead to a complete or near complete absence of
WASp expression. In XLT, the phenotype is generally milder as
the mutations lead to a partial loss of WASp activity, although
the precise link between residual WASp activity and disease
severity is not clearly dened (Jin et al., 2004; Albert et al.,
2010; Thrasher and Burns, 2010). Indeed, exceptions to the rela-
tionship between disease severity and residual WASp expression
do exist. For example, mutations that specically block WASp
activation of the ARP2/3 complex (Worth, 2013. Unpublished
data, personal communication.) result in normal WASp expres-
sion levels, but severe disease phenotype. XLN is the third
disease attributed to mutations in the WAS gene, but rather
than the loss of WASp activity seen in WAS and XLT, there is
an activation of WASp with disruption of the normal autoinhi-
bited conrmation, leading to excessive activity and uncon-
trolled actin polymerization (Thrasher and Burns, 2010).
Migration Defects in WAS
Establishment of the Hematopoietic System in the Bone Marrow
The hematopoietic system initially develops in the fetal liver,
with WASp expressed even at the very earliest stages of hemato-
poiesis (Parolini et al., 1997). Before birth, the entire hemato-
poietic system transfers to the bone marrow (Ciriza et al.,
2013). Evidence from female carriers of WAS, and female
WAS mice, suggests that WASp is required for the efcient
migration of the developing hematopoietic system from the
liver to the bone marrow (Greer et al., 1989; Lacout et al.,
2003). Because female cells have two copies of the
X-chromosome, one of which is always inactivated, it is
possible to test if there is preferential inactivation of the X-chro-
mosome containing the defective WAS gene. Initially during
development of the hematopoietic system in mice, there is
a random inactivation of the X-chromosome in fetal hemato-
poietic cells, with some cells expressing wild-type WAS and
some expressing mutant WAS. However, after migration
of the hematopoietic system to the bone marrow,
X-chromosome inactivation is nonrandom, favoring inactiva-
tion of the defective WAS X-chromosome. This demonstrates
a distinct homing advantage in WAS normal hematopoietic
progenitors. However, as WAS patients and mice have normal
numbers of hematopoietic bone marrow cells, the migration
deciency is not absolute. Cells expressing normal WASp
have a migration and homing advantage, so they establish in
the bone marrow before the WASp mutants. In the absence
of competition from WASp procient cells, the WASp mutants
still establish a full hematopoietic system in the bone marrow.
Phagocytic Cell Migration
The formation of branched (dendritic) actin networks through
the regulated activation of WASp is central to a variety of
immune functions. In phagocytic cells, these dendritic
networks are used to migrate toward, capture and phagocytose
invading pathogens, and also in the immune synapse formed
during intercellular interactions between phagocytes and
lymphocytes. Macrophages and neutrophils use the force
generated by a growing dendritic actin network to form lamel-
lipodia and drive the cell forward during migration (Krause
and Gautreau, 2014; Figure 1(b)). Additionally, small
dense actin structures called podosomes are formed by
WASp-mediated ARP2/3 activation in dendritic cells (DCs)
and macrophages (Olivier et al., 2006). These podosomes are
surrounded by vinculin and other adhesion molecules, and
facilitate adhesion of migrating cells to surrounding tissue
(Burns et al., 2004). The loss of WASp activity severely impedes
the migration of these phagocytic cells, with poor-chemotactic
response to a variety of chemoattractants including bacterial
peptides and host-produced chemokines and cytokines (Ochs
et al., 1980; Badolato et al., 1998; Cvejic et al., 2008; Snapper
et al., 2005; Zhang et al., 2006; Zicha et al., 1998).
The poor-chemotactic response is due to the inability to
restructure the actin cytoskeleton in response to signals from
these chemoattractants. The lack of podosome formation
(Jones et al., 2002; Linder et al., 1999; Tsuboi, 2007; Zhang
et al., 2006) prevents the vinculin-mediated integrin clustering
required for efcient adhesion to surrounding tissues (Burns
et al., 2004; Tsuboi and Meerloo, 2007), meaning the cells
have reduced traction to migrate. Combined with the inef-
cient formation of dendritic actin networks (Ishihara et al.,
2012), the lack of traction and force generation due to the
absence of WASp activity leaves phagocytic cells poorly equip-
ped to migrate toward and capture pathogens.
DC Migration
DCs are phagocytic cells of the innate immune system that
form the link between innate and adaptive immunity. They
phagocytose and process antigens in order to present these
 Immune Deficiency j WiskottAldrich Syndrome, Leukocyte Adhesion Deficiency, and Other Migration Defects
antigens to lymphocytes of the adaptive immune system. This
whole process is heavily reliant on migration. DCs must
migrate to a site of infection, phagocytose, and process antigen,
then migrate to lymph nodes and spleen to present antigen to
lymphocytes. The migration defects present in macrophages
and neutrophils also apply to DCs. Failure to produce stable
lamellipodia and the absence of podosomes to direct integrin
clustering results in poor adhesion to intercellular adhesion
molecule-1 on the endothelium (Binks et al., 1998; Bouma
et al., 2007; Burns et al., 2004, 2001; de Noronha et al.,
2005; Olivier et al., 2006), and reduced traction. Even if DCs
do succeed in migrating to inammatory sites, they subse-
quently fail to correctly localize in the lymph nodes and spleen
(Bouma et al., 2007; de Noronha et al., 2005). Together these
migratory defects lead to an extremely inefcient activation of
the adaptive immune system in WAS patients. The eczema
that is characteristic of WAS may also result from poor DC
migration, as the slowly migrating DCs may mature before
reaching the lymph nodes, triggering inammation in other-
wise healthy tissue.
Lymphocyte Migration
The hallmark defect in WAS is the abnormal formation of the
immune synapse between antigen-presenting cells and
lymphocytes (Gallego et al., 1997; Molina et al., 1993; Snapper
et al., 1998; Zhang et al., 1999). However, migratory de-
ciencies in both these cell types also contribute to the WAS
phenotype. WASp-decient T cells show poor adhesion (so
lack traction) and fail to migrate in response to chemokines
such as CCL19 and CCL21 (Snapper et al., 2005). Even after
the suboptimal activation and proliferation of T cells by DCs,
the few resulting activated T cells have poor homing to the
inammation site (Bouma et al., 2009). Similarly B lympho-
cytes adhere poorly, fail to polarize the cytoskeleton, and
migrate inefciently toward the chemokine CXCL13 and sphin-
gosine-1-phosphate (Westerberg et al., 2001, 2005; Ansel et al.,
2000; Meyer-Bahlburg et al., 2008; Park et al., 2005).
In addition to the role of podosomes in adhesion to
surrounding tissue, studies in lymphocytes revealed a novel
role for podosomes during migration through the endothe-
lium. Lymphocytes extend invasive protrusions with a podo-
some at their core that probe the surface of the endothelium
to nd sites permissive to transmigration. They then extend
the podosome directly through an endothelial cell forming
a pore through which the lymphocyte migrates across the endo-
thelium. This process is dependent on WASp (Carman et al.,
2007), and is very likely to also play a role in transendothelial
migration in a variety of immune cells (Carman and Springer,
2008).
Summary
The basis for the diverse symptoms seen in WAS and XLT is
a complex mix of defects in almost all immune cell lineages,
many of which may be directly related to migration. The migra-
tory defects are not absolute: WASp-decient cells are able to
migrate, but do so with low speed and poor directionality.
Slow migration of innate immune cells to sites of infection
allows more time for infections to develop. The lack of inltra-
tion of innate immune cells means there are few cells present to
release inammatory cytokines, so recruitment of further
419
immune cells is inefcient. Recruitment of professional antigen
presenting cells at inammatory sites and then delivery of
antigen to the adaptive arm of the immune system are similarly
perturbed. This is then further compounded by the poor migra-
tion of activated adaptive immune cells such as lymphocytes
and natural killer cells. It is the cumulative effect of poor migra-
tion across all hematopoietic lineages that combine to produce
the WAS phenotype.
Other Actin CytoskeletalRelated Migratory Defects
X-Linked Neutropenia
In 2001, a disorder was described that was the result of a novel
mutation in the WAS gene that resulted in an L270P mutation in
the GBD of WASp (Devriendt et al., 2001). Patients with this
WAS mutation suffer from severe recurrent bacterial infections
due to a profound neutropenia (Table 1). There are now four
naturally occurring mutations all clustered within the GBD of
WASp that give rise to the same disease (Ancliff et al., 2006;
Beel et al., 2009; Thrasher and Burns, 2010). These mutations
produce a WASp that has lost its autoinhibited conformation,
and activates the ARP2/3 complex indiscriminately without
the need for any activation signal. This leads to excessive ectopic
F-actin resulting in neutropenia due to massive apoptosis of
maturing neutrophils (Ancliff et al., 2006; Moulding et al.,
2007).
The presence of excess F-actin alters the mechanical proper-
ties of the cell (Moulding et al., 2007, 2012), and this in turn
has an impact on migration. In model systems where constitu-
tively active WASp is expressed in myeloid cell lines, migration
in response to the bacterial chemoattractant fMLP is far slower
than controls (Record et al., 2013. Unpublished observations.).
Surprisingly, despite the slow migration, the directionality of
these cells toward the chemoattractant is improved. It is likely
that the slow migration and improved directionality are attribut-
able to the decreased elasticity of these cells, where the inability
to rapidly restructure the actin cytoskeleton results in slow
migration and fewer direction changes.
DOCK8 Deciency
In 2009, a new severe combined immunodeciency (SCID)
was described with the discovery of mutations in the
DOCK8 gene in patients previously diagnosed with an auto-
somal recessive form of hyper IgE syndrome (Zhang et al.,
2009; Engelhardt et al., 2009). Unlike WAS, which is expressed
solely in the immune system, DOCK8 is expressed in most
tissues, but is most abundant in hematopoietic cells (Ruusala
and Aspenstrom, 2004). DOCK8 regulates the actin cytoskel-
eton through its role as a guanine exchange factor, converting
GDP to GTP to activate Rho GTPases. One of the Rho GTPases
activated by DOCK8 is Cdc42, which in turn activates WASp
(and other cytoskeletal regulators) (Miyamoto and Yamauchi,
2010). As a key regulator of the actin cytoskeleton, the absence
of DOCK8 causes a broad range of immune cell defects.
There are relatively few reports of specic migration defects
due to DOCK8 deciency, but where migration has been
assessed, it is similar to the defects seen in WAS. DCs show
cytoskeletal reorganization defects and slow migration through
420 Immune Deficiency j WiskottAldrich Syndrome, Leukocyte Adhesion Deficiency, and Other Migration Defects
tissue to infections and lymph nodes (Harada et al., 2012). The
cytoskeletal defects in WAS are also mirrored in DOCK8-de-
cient natural killer cells, with failure to polarize the actin cyto-
skeleton and a lack of integrin clustering (Mizesko et al., 2013).
While many of the cellular defects in DOCK8 deciency are
shared with WAS, the SCID in DOCK8 deciency has a far
broader clinical impact (Table 1), presumably as DOCK8
controls many cytoskeletal regulators in addition to WASp
including N-WASp.
Exceptionally Rare Actin Cytoskeletal Immunodeciencies
WIP Deficiency
WASp requires the chaperone WIP to stabilize the protein and
protect it from proteolysis (Chou et al., 2006; de la Fuente
et al., 2007; Konno et al., 2007). Therefore, loss of WIP expres-
sion may give rise to a WASp deciency. In 2012, a report
described a female patient with all the symptoms of WAS
(Lanzi et al., 2012). The patient had normal WAS gene
sequence and mRNA, but lacked WASp expression. Further
investigation revealed a mutation in the WIP gene resulting
in a truncated protein that was unable to bind to and stabilize
WASp. This novel immunodeciency most likely has all the
migratory defects present in WAS, but the additional loss of
WIP may lead to further complications. Recent reports demon-
strate that independent of its function stabilizing WASp, WIP
also binds actin and stabilizes the cytoskeleton to aid T cell
migration, adhesion, and homing (Massaad et al., 2014).
Coronin 1A Mutations
In 2008, a spontaneously occurring disease in mice, peripheral T
celldecient mice, and a novel SCID were shown to be a result
of a Coronin 1A mutation (Shiow et al., 2008). The major defect
in Coronin 1Aassociated SCID is an absence of peripheral T
cells, despite normal thymic development. This has been
explained as a migration defect, where T cells are unable to
exit the thymus. Since the initial report, a total of seven cases
of Coronin 1A SCID have been identied, all sharing the same
thymic egress defect (Punwani et al., 2015). Coronin 1A is
involved in actin cytoskeletal remodeling, but its exact mode
of action remains unclear (Chan et al., 2011). It can bind the
plasma membrane, F-actin, the ARP2/3 complex, other actin
regulators such as colin and actin inhibitory protein 1, and
signaling molecules such as PLC (Punwani et al., 2015). Coronin
1A can promote actin disassembly by holding the ARP2/3
complex in an inactive formation (Machesky et al., 1997), or
triggering colin-mediated actin depolymerization (Kueh et al.,
2008). The lack of Coronin 1A activity leads to increased
F-actin content, and this was initially thought to be the cause
of the failure of thymic egress (Fger et al., 2006). However,
the signaling through PLC may be more important, with a lack
of calcium signaling and cytoskeletal restructuring leading to T
cell migration defects and apoptosis (Mueller et al., 2011,
2008). Coronin 1A deciency highlights the need for migration
not just in getting to and from sites of infection, but also in the
successful development of functional immune cells.
Rho GTPase Mutations
The Rho GTPase pathway is the main regulator of actin cytoskel-
etal dynamics (Heasman and Ridley, 2008; Mulloy et al., 2010),
with defects in upstream regulators such as DOCK8 and down-
stream effectors such as WASp leading to SCID. The Rho GTPases
sit in the middle of the pathway, transducing signals from the
upstream regulators to the downstream effectors, so it is not
surprising that PIDs can result from mutations in Rho GTPase
genes. In 2000, two patients were independently found to
have a PID-termed neutrophil immunodeciency syndrome
with mutations in the RAC2 gene (Ambruso et al., 2000;
Williams et al., 2000). Rac2 is only expressed in the immune
lineage, and is particularly abundant in neutrophils. A third
case was described in 2011 (Accetta et al., 2011), with all three
cases sharing an identical D57N mutation resulting in a domi-
nant negative protein. Neutrophils expressing dominant nega-
tive Rac2 are unable to restructure and polarize the actin
cytoskeleton so show very poor chemotaxis. Thymic T cell
production is also perturbed, a phenotype shared with Coronin
1A SCID, possibly due to defective integrin function. The
extreme rarity of this disorder has limited patient studies.
However, studies in mice have shown that Rac2 mutations
have a broad impact on many immune cell functions, with
migratory and other defects in hematopoietic stem cells
(HSCs) (Gu et al., 2003), B and T lymphocytes (Croker et al.,
2002; Li et al., 2000; Walmsley et al., 2003), macrophages
(Yamauchi et al., 2004), and eosinophils (Fulkerson et al.,
2005).
In 2012, a loss of function mutation in the RhoH gene was
identied as a novel cause of epidermodysplasia verruciformis
(Crequer et al., 2012). This disease is characterized by persis-
tent EV-human papilloma virus infections, and T cell homing
in these two patients is decient, due to lack of b7 integrin
expression. The cellular basis of this disorder is probably a result
of excessive actin production, as RhoH inhibition of the actin
polymerizing signaling from Rac2 is lost (Chae et al., 2008;
Gu et al., 2005).
These two Rho GTPase disorders result in opposing cyto-
skeletal defects, loss of F-actin production in Rac2 deciency,
and excessive actin production in RhoH deciency. This high-
lights the need for delicate regulation of the actin cytoskeleton
for efcient immune cell function.
Neutrophil Actin Dysfunction Syndrome
In 1991, an immunodeciency affecting three siblings was
described with severe neutrophil migration defects (Coates
et al., 1991). While the genetic basis for the disease remains
unknown, two proteins are overexpressed, a 47 kDa protein
later identied as LSP1, and an unknown 87 kDa protein
(Howard et al., 1994). LSP1 is an actin bundling protein that
organizes F-actin into bundles in lamellipodia, lopodia, and
membrane rufes (Jongstra-Bilen and Jongstra, 2006). Loss of
LSP1 expression enhances chemotaxis in mouse models
(Jongstra-Bilen et al., 2000), suggesting that the overexpression
of LSP1 in neutrophil actin dysfunction syndrome may impede
neutrophil migration through excessive actin bundling and an
inability to restructure the cytoskeleton.
Signaling and Adhesion Defects
All of the migratory SCIDs described above involve defects in
the control of actin cytoskeletal restructuring. Migration is
 Immune Deficiency j WiskottAldrich Syndrome, Leukocyte Adhesion Deficiency, and Other Migration Defects
driven by cytoskeletal restructuring, but is triggered in response
to external stimuli and signaling, and requires adhesion
between the migrating cell and its environment. Defects
in both of these processes also lead to migration
immunodeciencies.
Warts, Hypogammaglobulinemia, Infections,
and Myelokathexis
Warts, hypogammaglobulinemia, infections, and myeloka-
thexis (WHIM) was rst described in 1990 and is characterized
by recurrent bacterial infections and the development of
a susceptibility to HPV in the teenage years leading to warts
on the hands and feet, and neutropenia and monocytopenia
(Wetzler et al., 1990; Al Ustwani et al., 2014). WHIM is caused
by mutations in the chemokine receptor CXCR4, generating an
overactive receptor. While CXCR4 is expressed in many cells
and tissues, mutations manifest primarily as an immunode-
ciency, perhaps indicative of the particular dependence of the
immune system on migration.
CXCR4 is the receptor for the chemokine CXCL12, which
is strongly expressed on stromal cells in the bone marrow
and acts to retain HSCs. The overactivation of the CXCR4
receptor on neutrophils (and monocytes) inhibits the migra-
tion of these cells out of the bone marrow, leading to neutro-
penia and monocytopenia. T cell and B cell development are
also perturbed, although this is a result of defective migra-
tion within the thymus, spleen, and lymph nodes, rather
than entrapment within the bone marrow. In this syndrome,
the migration machinery is intact, but the faulty signaling
results in inappropriate migratory signals and immunode-
ciency. Recently, one patient with WHIM syndrome was
cured by a spontaneous chromothripsis (McDermott et al.,
2015). Here, deletion of the mutant allele allowed selective
repopulation of the myeloid compartment and resolution
of symptoms.
Leukocyte Adhesion Deciency Syndrome
In order for phagocytes to reach a site of infection, they must
rst attach to and migrate through the endothelium of the
blood vessel wall. A group of related defects called leukocyte
adhesion deciency (LAD) form a subset of PIDs where
adhesion to the endothelium is disrupted, preventing extrav-
asation from the bloodstream into the surrounding tissues
(van de Vijver et al., 2013). The rst type of LAD was
described in 1980 (Crowley et al., 1980), as a disorder char-
acterized by recurrent bacterial infections and neutrophilia
in which neutrophils are unable to adhere and spread. The
gene was subsequently identied as ITGB2, the common b-
chain of the leukocyte integrin CD18, with at least 86
different point mutations described in LAD I patients (van
de Vijver et al., 2012). CD18 is required for the formation
of a rm adhesion to the endothelium, and lack of expres-
sion severely impairs endothelial transmigration (Fiorini
et al., 2002).
LAD II is an extremely rare disorder rst described in
1992 (Etzioni et al., 1992), in which the SLC35C1 gene
encoding for a Golgi GDP-fucose transport protein is
mutated resulting in loss of expression. This leads to a lack
421
of fucose modication on certain cell surface glycoproteins
on leukocytes and endothelial cells that serve as ligand for
the selectin family of surface receptors (van de Vijver et al.,
2013). Selectins are important for the initial attachment
and rolling of leukocytes along the endothelial cells of the
vessel wall. Immunologically, LAD II is a less-severe disease
than LAD I, as some extravasation still occurs; however,
other severe developmental and mental defects are also
present due to the wider role of fucosylation outside of
the immune system.
LAD III was rst described in 1997 (Kuijpers et al., 1997), and
is now known to be caused by mutations in the FERMT3 gene
encoding Kindlin-3. This protein is involved in inside-out
signaling that is important in integrin activation and the forma-
tion of high-afnity attachment to their ligands (van de Vijver
et al., 2013). LAD III is a severe disorder, with bleeding compli-
cations due to loss of integrin activation on platelets, and has
a high-mortality rate.
Concluding Remarks
The PIDs presented here together show how defects in migra-
tion affect almost every aspect of the immune response. Migra-
tion is required to establish the hematopoietic system in the
bone marrow, and the resulting mature hematopoietic cells
must then be able to leave the bone marrow and travel
throughout the host tissues. T cell development in the thymus
depends on correct thymic localization of developing cells, and
then migration drives the egress of these cells from the thymus.
Lymphocyte activation in the spleen and lymph nodes is
impeded by poor-migratory capacity, and homing of activated
lymphocytes to inammatory sites is dependent on active
migration. Attachment to and migration through the endothe-
lium to leave the bloodstream and migrate to an infection is
often defective in migratory immunodeciencies, and the
subsequent journey through tissue to the infection site is also
perturbed.
Any one of these migratory deciencies is sufcient to cause
disease, as the immune response is an intricate and highly
interdependent process. Failure at any level has knock on
effects, and multilevel failure as seen in WAS, combine to
produce severe defects, resulting in immunodeciency, autoim-
munity, and predisposition to cancer. The wide ranging clinical
impact of these migration immunodeciencies limits treatment
options, with the only denitive treatment often being HSC
transplantation.
See also: Anatomy and Microanatomy of the Immune System:
Blood Vascular Endothelial Adhesion Molecules; Effector T
Lymphocyte Migration to and Within Non-Lymphoid Tissues;
Endothelial Adhesion Molecules in the Lymphatic Vasculature;
Leukocyte Adhesion Molecules; Lymph Node Structure; Roles
of Chemokines in Immune Cell Trafcking to Lymphoid
Tissues; S1P and LPA: Regulators of Immune Cell Egress and
Ingress in Lymphoid Tissues; Structure and Function of the
Bone Marrow Hematopoietic Niche; The Spleen; Thymic
Microenvironments: Development, Organization, and Function.
Cells of the Innate Immune System: Dendritic Cells and
422 Immune Deficiency j WiskottAldrich Syndrome, Leukocyte Adhesion Deficiency, and Other Migration Defects
Dendritic Cell Subsets; ILC2 in Immunity; Macrophage
Activation and Polarization; Natural Killer Cells; Neutrophils
Role in Innate Immunity; The Role of Invariant NKT Cells in
Immunity. Development of T Cells and Innate Lymphoid Cells:
CD4/CD8 Lineage Commitment; Control of Migration during
Intrathymic T Cell Development; Development of Group 2
Innate Lymphoid Cells; Development of Natural Killer Cells and
ILC1; Development of Regulatory T Cells in the Thymus; Innate
Lymphoid Cells Type 3; Orchestration of T Cell Development by
Common g Chain Cytokines; Production of the Semi-Invariant
TCR and PLZF Function in Innate Programming of iNKT Cells;
Transcriptional Regulation of T Cell Lineage Commitment;
Transcriptional and Microenvironmental Regulation of gd T Cell
Development. Immune Deciency: Combined T Cell and B Cell
Deciency SCID Forms: TB; Primary Immunodeciencies:
Clinical and Biological Guidelines. MHC Structure and Function:
Origin and Processing of MHC Class II Ligands; Origin and
Processing of MHC-I Ligands. Myeloid and B Cell
Development: Adult Hematopoiesis; Marginal Zone B Cell
Development; Myelopoiesis; Ontogeny of the Hematopoietic
System. Signal Transduction: Immunological Synapses; Signal
Transduction by the B Cell Antigen Receptor; Signaling of
Phagocytosis; TCR Signaling: Proximal Signaling. Structure
and Function of Diversifying Receptors: Organization and
Rearrangement of TCR Loci; Structure and Function of TCRab
Receptors; Structure and Function of TCRgd Receptors.
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